Selected Publications
Marina Miñarro-Lleonar Andrea Bertran-Mostazo, Jorge Duro Xavier Barril Jordi Juárez-Jiménez Theoretical and Computational Chemistry, 2022. @article{Miñarro-Lleonar2022, title = {Lenalidomide stabilizes protein-protein complexes by turning labile intermolecular H-bonds into robust interactions}, author = {Marina Miñarro-Lleonar, Andrea Bertran-Mostazo, Jorge Duro, Xavier Barril, Jordi Juárez-Jiménez}, url = {https://chemrxiv.org/engage/chemrxiv/article-details/633c4d21e665bd743d1d595a}, doi = {10.26434/chemrxiv-2022-3kpgm}, year = {2022}, date = {2022-10-06}, journal = { Theoretical and Computational Chemistry}, abstract = {Targeted protein degradation (TPD) is emerging as a very promising strategy to modulate protein activities in several diseases, spearheaded by anti–myeloma drugs lenalidomide and pomalidomide. It has been recently demonstrated that the mechanism of action of these drugs involves the increased degradation of several proteins, including the transcription factors Ikaros and Aiolos as well as the enzyme Caseine Kinase 1 alpha (CK1a). It has been shown that lenalidomide and pomalidomide are able to stabilize the complex between the E3 ligase Cereblon (CRL4CRBN) and the aforementioned proteins, while, remarkably, the stability of the protein-protein interaction is very low. Even though the structures for these complexes have been determined, there are no evident interactions that can account for the high formation efficiency of the ternary complex. In this work, we have leveraged Molecular Dynamics to shed light into the molecular determinants underlying the stabilization effect exerted by lenalidomide in the complex between CRL4CRBN and CK1a. Furthermore, we evaluated the effect that different mutations of CK1a in the stability of the ternary complex CRL4CRBN–lenalidomide–CK1a and provide a thermodynamic and kinetic rational for the stabilization effect. These results pave the way to further understand cooperativity effects in drug–induced protein–protein complexes and could help in the future design of improved targeted molecular degraders.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Targeted protein degradation (TPD) is emerging as a very promising strategy to modulate protein activities in several diseases, spearheaded by anti–myeloma drugs lenalidomide and pomalidomide. It has been recently demonstrated that the mechanism of action of these drugs involves the increased degradation of several proteins, including the transcription factors Ikaros and Aiolos as well as the enzyme Caseine Kinase 1 alpha (CK1a). It has been shown that lenalidomide and pomalidomide are able to stabilize the complex between the E3 ligase Cereblon (CRL4CRBN) and the aforementioned proteins, while, remarkably, the stability of the protein-protein interaction is very low. Even though the structures for these complexes have been determined, there are no evident interactions that can account for the high formation efficiency of the ternary complex. In this work, we have leveraged Molecular Dynamics to shed light into the molecular determinants underlying the stabilization effect exerted by lenalidomide in the complex between CRL4CRBN and CK1a. Furthermore, we evaluated the effect that different mutations of CK1a in the stability of the ternary complex CRL4CRBN–lenalidomide–CK1a and provide a thermodynamic and kinetic rational for the stabilization effect. These results pave the way to further understand cooperativity effects in drug–induced protein–protein complexes and could help in the future design of improved targeted molecular degraders. |
Piticchio, Serena; Martínez-Cartró, Míriam; Scaffidi, Salvatore; Rachman, Moira; Rodriguez-Arevalo, Sergio; Sanchez-Arfelis, Ainoa; Escolano, Carmen; Picaud, Sarah; Krojer, Tobias; Filippakopoulos, Panagis; von Delft, Frank; Galdeano, Carles; Barril, Xavier Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space Journal of Medicinal Chemistry, 2021. @article{Serena_2021, title = {Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space}, author = {Piticchio, Serena G. and Martínez-Cartró, Míriam and Scaffidi, Salvatore and Rachman, Moira and Rodriguez-Arevalo, Sergio and Sanchez-Arfelis, Ainoa and Escolano, Carmen and Picaud, Sarah and Krojer, Tobias and Filippakopoulos, Panagis and von Delft, Frank and Galdeano, Carles and Barril, Xavier}, url = {https://doi.org/10.1021/acs.jmedchem.1c01108}, doi = {10.1021/acs.jmedchem.1c01108}, year = {2021}, date = {2021-12-13}, journal = {Journal of Medicinal Chemistry}, abstract = {Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD. |
Majewski, Maciej; Ruiz-Carmona, Sergio; Barril, Xavier Communications Chemistry, 2 ( 110), 2019, ISSN: 2399-3669. @article{Maciej2019, title = {An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder}, author = {Maciej Majewski and Sergio Ruiz-Carmona and Xavier Barril }, url = {https://doi.org/10.1038/s42004-019-0205-5}, doi = {10.1038/s42004-019-0205-5}, issn = {2399-3669}, year = {2019}, date = {2019-09-17}, journal = {Communications Chemistry}, volume = {2}, number = { 110}, abstract = {The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 drug-like and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 drug-like and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design. |
Ruiz-Carmona, Sergio; Schmidtke, Peter; Luque, Javier; Baker, Lisa; Matassova, Natalia; Davis, Ben; Roughley, Stephen; Murray, James; Hubbard, Rod; Barril, Xavier Dynamic undocking and the quasi-bound state as tools for drug discovery Nature Chemistry, 9 (3), pp. 201–206 , 2016, ISSN: 1755-4349, (Link to tutorial: www.ub.edu/bl/undocking). @article{RuizDuck2016, title = { Dynamic undocking and the quasi-bound state as tools for drug discovery}, author = {Sergio Ruiz-Carmona and Peter Schmidtke and F. Javier Luque and Lisa Baker and Natalia Matassova and Ben Davis and Stephen Roughley and James Murray and Rod Hubbard and Xavier Barril}, url = {http://dx.doi.org/10.1038/nchem.2660}, issn = {1755-4349}, year = {2016}, date = {2016-11-14}, journal = {Nature Chemistry}, volume = {9}, number = {3}, pages = {201–206 }, abstract = {There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%.}, note = {Link to tutorial: www.ub.edu/bl/undocking}, keywords = {}, pubstate = {published}, tppubtype = {article} } There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%. |
Ruiz-Carmona, Sergio; Alvarez-Garcia, Daniel; Foloppe, Nicolas; a. Garmendia-Doval, Beatriz; Juhos, Szilveszter; Schmidtke, Peter; Barril, Xavier; Hubbard, Roderick; Morley, David rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids PLoS Computational Biology, 10 (4), pp. e1003571, 2014, ISSN: 1553-7358. @article{Ruiz-Carmona2014, title = {rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids}, author = { Sergio Ruiz-Carmona and Daniel Alvarez-Garcia and Nicolas Foloppe and a. Beatriz Garmendia-Doval and Szilveszter Juhos and Peter Schmidtke and Xavier Barril and Roderick E. Hubbard and S. David Morley}, editor = {Prlic, Andreas}, url = {http://dx.plos.org/10.1371/journal.pcbi.1003571}, issn = {1553-7358}, year = {2014}, date = {2014-04-01}, journal = {PLoS Computational Biology}, volume = {10}, number = {4}, pages = {e1003571}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Álvarez-García, Daniel; Barril, Xavier Journal of Medicinal Chemistry, (57), 2014. @article{Alvarez-Garcia2014jmc, title = {Molecular Simulations with Solvent Competition Quantify Water Displaceability and Provide Accurate Interaction Maps of Protein Binding Sites}, author = { Daniel Álvarez-García and Xavier Barril}, url = {http://pubs.acs.org/doi/abs/10.1021/jm5010418}, year = {2014}, date = {2014-01-01}, journal = {Journal of Medicinal Chemistry}, number = {57}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Schmidtke, Peter; Luque, Javier; Murray, James; Barril, Xavier Shielded hydrogen bonds as structural determinants of binding kinetics: application in drug design. Journal of the American Chemical Society, 133 (46), pp. 18903–10, 2011, ISSN: 1520-5126. @article{Schmidtke2011a, title = {Shielded hydrogen bonds as structural determinants of binding kinetics: application in drug design.}, author = { Peter Schmidtke and F Javier Luque and James B Murray and Xavier Barril}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21981450 http://pubs.acs.org/doi/abs/10.1021/ja207494u}, issn = {1520-5126}, year = {2011}, date = {2011-11-01}, journal = {Journal of the American Chemical Society}, volume = {133}, number = {46}, pages = {18903--10}, abstract = {Time scale control of molecular interactions is an essential part of biochemical systems, but very little is known about the structural factors governing the kinetics of molecular recognition. In drug design, the lifetime of drug-target complexes is a major determinant of pharmacological effects but the absence of structure-kinetic relationships precludes rational optimization of this property. Here we show that almost buried polar atoms-a common feature on protein binding sites-tend to form hydrogen bonds that are shielded from water. Formation and rupture of this type of hydrogen bonds involves an energetically penalized transition state because it occurs asynchronously with dehydration/rehydration. In consequence, water-shielded hydrogen bonds are exchanged at slower rates. Occurrence of this phenomenon can be anticipated from simple structural analysis, affording a novel tool to interpret and predict structure-kinetics relationships. The validity of this principle has been investigated on two pairs of Hsp90 inhibitors for which detailed thermodynamic and kinetic data has been experimentally determined. The agreement between macroscopic observables and molecular simulations confirms the role of water-shielded hydrogen bonds as kinetic traps and illustrates how our finding could be used as an aid in structure-based drug discovery.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Time scale control of molecular interactions is an essential part of biochemical systems, but very little is known about the structural factors governing the kinetics of molecular recognition. In drug design, the lifetime of drug-target complexes is a major determinant of pharmacological effects but the absence of structure-kinetic relationships precludes rational optimization of this property. Here we show that almost buried polar atoms-a common feature on protein binding sites-tend to form hydrogen bonds that are shielded from water. Formation and rupture of this type of hydrogen bonds involves an energetically penalized transition state because it occurs asynchronously with dehydration/rehydration. In consequence, water-shielded hydrogen bonds are exchanged at slower rates. Occurrence of this phenomenon can be anticipated from simple structural analysis, affording a novel tool to interpret and predict structure-kinetics relationships. The validity of this principle has been investigated on two pairs of Hsp90 inhibitors for which detailed thermodynamic and kinetic data has been experimentally determined. The agreement between macroscopic observables and molecular simulations confirms the role of water-shielded hydrogen bonds as kinetic traps and illustrates how our finding could be used as an aid in structure-based drug discovery. |
Schmidtke, Peter; Barril, Xavier Journal of medicinal chemistry, 53 (15), pp. 5858–67, 2010, ISSN: 1520-4804. @article{Schmidtke2010, title = {Understanding and predicting druggability. A high-throughput method for detection of drug binding sites.}, author = { Peter Schmidtke and Xavier Barril}, url = {https://doi.org/10.1021/jm100574m}, doi = {10.1021/jm100574m}, issn = {1520-4804}, year = {2010}, date = {2010-08-01}, journal = {Journal of medicinal chemistry}, volume = {53}, number = {15}, pages = {5858--67}, abstract = {Druggability predictions are important to avoid intractable targets and to focus drug discovery efforts on sites offering better prospects. However, few druggability prediction tools have been released and none has been extensively tested. Here, a set of druggable and nondruggable cavities has been compiled in a collaborative platform ( http://fpocket.sourceforge.net/dcd ) that can be used, contributed, and curated by the community. Druggable binding sites are often oversimplified as closed, hydrophobic cavities, but data set analysis reveals that polar groups in druggable binding sites have properties that enable them to play a decisive role in ligand recognition. Finally, the data set has been used in conjunction with the open source fpocket suite to train and validate a logistic model. State of the art performance was achieved for predicting druggability on known binding sites and on virtual screening experiments where druggable pockets are retrieved from a pool of decoys. The algorithm is free, extremely fast, and can effectively be used to automatically sieve through massive collections of structures ( http://fpocket.sourceforge.net ).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Druggability predictions are important to avoid intractable targets and to focus drug discovery efforts on sites offering better prospects. However, few druggability prediction tools have been released and none has been extensively tested. Here, a set of druggable and nondruggable cavities has been compiled in a collaborative platform ( http://fpocket.sourceforge.net/dcd ) that can be used, contributed, and curated by the community. Druggable binding sites are often oversimplified as closed, hydrophobic cavities, but data set analysis reveals that polar groups in druggable binding sites have properties that enable them to play a decisive role in ligand recognition. Finally, the data set has been used in conjunction with the open source fpocket suite to train and validate a logistic model. State of the art performance was achieved for predicting druggability on known binding sites and on virtual screening experiments where druggable pockets are retrieved from a pool of decoys. The algorithm is free, extremely fast, and can effectively be used to automatically sieve through massive collections of structures ( http://fpocket.sourceforge.net ). |
Seco, Jesus; Luque, Javier; Barril, Xavier Binding site detection and druggability index from first principles. Journal of medicinal chemistry, 52 (8), pp. 2363–71, 2009, ISSN: 1520-4804. @article{Seco2009, title = {Binding site detection and druggability index from first principles.}, author = { Jesus Seco and F Javier Luque and Xavier Barril}, url = {http://pubs.acs.org/doi/abs/10.1021/jm801385d}, issn = {1520-4804}, year = {2009}, date = {2009-04-01}, journal = {Journal of medicinal chemistry}, volume = {52}, number = {8}, pages = {2363--71}, abstract = {In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using molecular dynamics with a binary solvent. Furthermore, analysis of the simulations give direct access to interaction free energies between the protein and small organic molecules, which can be used to detect binding sites and to predict the maximal affinity that a drug-like molecule could attain for them. On a set of pharmacologically relevant proteins, we obtain good predictions for druggable sites as well as for protein-protein and low affinity binding sites. This is the first druggability index not based on surface descriptors and, being independent of a training set, is particularly indicated to study unconventional targets such as protein-protein interactions or allosteric binding sites.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using molecular dynamics with a binary solvent. Furthermore, analysis of the simulations give direct access to interaction free energies between the protein and small organic molecules, which can be used to detect binding sites and to predict the maximal affinity that a drug-like molecule could attain for them. On a set of pharmacologically relevant proteins, we obtain good predictions for druggable sites as well as for protein-protein and low affinity binding sites. This is the first druggability index not based on surface descriptors and, being independent of a training set, is particularly indicated to study unconventional targets such as protein-protein interactions or allosteric binding sites. |
All Publications
Marina Miñarro-Lleonar Andrea Bertran-Mostazo, Jorge Duro Xavier Barril Jordi Juárez-Jiménez Theoretical and Computational Chemistry, 2022. @article{Miñarro-Lleonar2022, title = {Lenalidomide stabilizes protein-protein complexes by turning labile intermolecular H-bonds into robust interactions}, author = {Marina Miñarro-Lleonar, Andrea Bertran-Mostazo, Jorge Duro, Xavier Barril, Jordi Juárez-Jiménez}, url = {https://chemrxiv.org/engage/chemrxiv/article-details/633c4d21e665bd743d1d595a}, doi = {10.26434/chemrxiv-2022-3kpgm}, year = {2022}, date = {2022-10-06}, journal = { Theoretical and Computational Chemistry}, abstract = {Targeted protein degradation (TPD) is emerging as a very promising strategy to modulate protein activities in several diseases, spearheaded by anti–myeloma drugs lenalidomide and pomalidomide. It has been recently demonstrated that the mechanism of action of these drugs involves the increased degradation of several proteins, including the transcription factors Ikaros and Aiolos as well as the enzyme Caseine Kinase 1 alpha (CK1a). It has been shown that lenalidomide and pomalidomide are able to stabilize the complex between the E3 ligase Cereblon (CRL4CRBN) and the aforementioned proteins, while, remarkably, the stability of the protein-protein interaction is very low. Even though the structures for these complexes have been determined, there are no evident interactions that can account for the high formation efficiency of the ternary complex. In this work, we have leveraged Molecular Dynamics to shed light into the molecular determinants underlying the stabilization effect exerted by lenalidomide in the complex between CRL4CRBN and CK1a. Furthermore, we evaluated the effect that different mutations of CK1a in the stability of the ternary complex CRL4CRBN–lenalidomide–CK1a and provide a thermodynamic and kinetic rational for the stabilization effect. These results pave the way to further understand cooperativity effects in drug–induced protein–protein complexes and could help in the future design of improved targeted molecular degraders.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Targeted protein degradation (TPD) is emerging as a very promising strategy to modulate protein activities in several diseases, spearheaded by anti–myeloma drugs lenalidomide and pomalidomide. It has been recently demonstrated that the mechanism of action of these drugs involves the increased degradation of several proteins, including the transcription factors Ikaros and Aiolos as well as the enzyme Caseine Kinase 1 alpha (CK1a). It has been shown that lenalidomide and pomalidomide are able to stabilize the complex between the E3 ligase Cereblon (CRL4CRBN) and the aforementioned proteins, while, remarkably, the stability of the protein-protein interaction is very low. Even though the structures for these complexes have been determined, there are no evident interactions that can account for the high formation efficiency of the ternary complex. In this work, we have leveraged Molecular Dynamics to shed light into the molecular determinants underlying the stabilization effect exerted by lenalidomide in the complex between CRL4CRBN and CK1a. Furthermore, we evaluated the effect that different mutations of CK1a in the stability of the ternary complex CRL4CRBN–lenalidomide–CK1a and provide a thermodynamic and kinetic rational for the stabilization effect. These results pave the way to further understand cooperativity effects in drug–induced protein–protein complexes and could help in the future design of improved targeted molecular degraders. |
Osvaldo Burastero Lucas A Defelipe, Gabriel Gola Nancy Tateosian Elias Lopez Camila Belen Martinena Juan Pablo Arcon Martín Dodes Traian Diana Wetzler Isabel Bento Xavier Barril Javier Ramirez Marcelo Marti Maria Garcia-Alai Adrián Turjanski Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors Journal of Medicinal Chemistry, 2022. @article{Burastero2022, title = {Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors}, author = {Osvaldo Burastero, Lucas A Defelipe, Gabriel Gola, Nancy L Tateosian, Elias D Lopez, Camila Belen Martinena, Juan Pablo Arcon, Martín Dodes Traian, Diana E Wetzler, Isabel Bento, Xavier Barril, Javier Ramirez, Marcelo A Marti, Maria M Garcia-Alai, Adrián G Turjanski}, url = {https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.1c02012}, doi = {https://doi.org/10.1021/acs.jmedchem.1c02012}, year = {2022}, date = {2022-06-23}, journal = {Journal of Medicinal Chemistry}, abstract = {Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein–ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis (Mtb). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein–ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis (Mtb). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages. |
Marina Miñarro-Lleonar Sergio Ruiz-Carmona, Daniel Alvarez-Garcia Peter Schmidtke Xavier Barril Development of an Automatic Pipeline for Participation in the CELPP Challenge International Journal of Molecular Sciences, 2022. @article{Marina_2022, title = {Development of an Automatic Pipeline for Participation in the CELPP Challenge}, author = {Marina Miñarro-Lleonar, Sergio Ruiz-Carmona, Daniel Alvarez-Garcia, Peter Schmidtke, Xavier Barril}, url = {https://doi.org/10.3390/ijms23094756}, doi = {10.3390/ijms23094756}, year = {2022}, date = {2022-04-26}, journal = {International Journal of Molecular Sciences}, abstract = {The prediction of how a ligand binds to its target is an essential step for Structure-Based Drug Design (SBDD) methods. Molecular docking is a standard tool to predict the binding mode of a ligand to its macromolecular receptor and to quantify their mutual complementarity, with multiple applications in drug design. However, docking programs do not always find correct solutions, either because they are not sampled or due to inaccuracies in the scoring functions. Quantifying the docking performance in real scenarios is essential to understanding their limitations, managing expectations and guiding future developments. Here, we present a fully automated pipeline for pose prediction validated by participating in the Continuous Evaluation of Ligand Pose Prediction (CELPP) Challenge. Acknowledging the intrinsic limitations of the docking method, we devised a strategy to automatically mine and exploit pre-existing data, defining—whenever possible—empirical restraints to guide the docking process. We prove that the pipeline is able to generate predictions for most of the proposed targets as well as obtain poses with low RMSD values when compared to the crystal structure. All things considered, our pipeline highlights some major challenges in the automatic prediction of protein–ligand complexes, which will be addressed in future versions of the pipeline.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The prediction of how a ligand binds to its target is an essential step for Structure-Based Drug Design (SBDD) methods. Molecular docking is a standard tool to predict the binding mode of a ligand to its macromolecular receptor and to quantify their mutual complementarity, with multiple applications in drug design. However, docking programs do not always find correct solutions, either because they are not sampled or due to inaccuracies in the scoring functions. Quantifying the docking performance in real scenarios is essential to understanding their limitations, managing expectations and guiding future developments. Here, we present a fully automated pipeline for pose prediction validated by participating in the Continuous Evaluation of Ligand Pose Prediction (CELPP) Challenge. Acknowledging the intrinsic limitations of the docking method, we devised a strategy to automatically mine and exploit pre-existing data, defining—whenever possible—empirical restraints to guide the docking process. We prove that the pipeline is able to generate predictions for most of the proposed targets as well as obtain poses with low RMSD values when compared to the crystal structure. All things considered, our pipeline highlights some major challenges in the automatic prediction of protein–ligand complexes, which will be addressed in future versions of the pipeline. |
Luis Pablo Avila-Barrientos Luis Fernando Cofas-Vargas, Guillermin Agüero-Chapin Enrique Hernández-García Sergio Ruiz-Carmona Norma Valdez-Cruz Mauricio Trujillo-Roldán Joachim Weber Yasser Ruiz-Blanco Xavier Barril Enrique García-Hernández Antibiotics, 2022. @article{Avila-Barrientos2022, title = {Computational Design of Inhibitors Targeting the Catalytic β Subunit of Escherichia coli FOF1-ATP Synthase}, author = {Luis Pablo Avila-Barrientos, Luis Fernando Cofas-Vargas, Guillermin Agüero-Chapin, Enrique Hernández-García, Sergio Ruiz-Carmona, Norma A Valdez-Cruz, Mauricio Trujillo-Roldán, Joachim Weber, Yasser B Ruiz-Blanco, Xavier Barril, Enrique García-Hernández}, url = { https://doi.org/10.3390/antibiotics11050557}, doi = {10.3390/antibiotics11050557}, year = {2022}, date = {2022-04-22}, journal = {Antibiotics}, abstract = {With the uncontrolled growth of multidrug-resistant bacteria, there is an urgent need to search for new therapeutic targets, to develop drugs with novel modes of bactericidal action. FoF1-ATP synthase plays a crucial role in bacterial bioenergetic processes, and it has emerged as an attractive antimicrobial target, validated by the pharmaceutical approval of an inhibitor to treat multidrug-resistant tuberculosis. In this work, we aimed to design, through two types of in silico strategies, new allosteric inhibitors of the ATP synthase, by targeting the catalytic β subunit, a centerpiece in communication between rotor subunits and catalytic sites, to drive the rotary mechanism. As a model system, we used the F1 sector of Escherichia coli, a bacterium included in the priority list of multidrug-resistant pathogens. Drug-like molecules and an IF1-derived peptide, designed through molecular dynamics simulations and sequence mining approaches, respectively, exhibited in vitro micromolar inhibitor potency against F1. An analysis of bacterial and Mammalia sequences of the key structural helix-turn-turn motif of the C-terminal domain of the β subunit revealed highly and moderately conserved positions that could be exploited for the development of new species-specific allosteric inhibitors. To our knowledge, these inhibitors are the first binders computationally designed against the catalytic subunit of FOF1-ATP synthase.}, keywords = {}, pubstate = {published}, tppubtype = {article} } With the uncontrolled growth of multidrug-resistant bacteria, there is an urgent need to search for new therapeutic targets, to develop drugs with novel modes of bactericidal action. FoF1-ATP synthase plays a crucial role in bacterial bioenergetic processes, and it has emerged as an attractive antimicrobial target, validated by the pharmaceutical approval of an inhibitor to treat multidrug-resistant tuberculosis. In this work, we aimed to design, through two types of in silico strategies, new allosteric inhibitors of the ATP synthase, by targeting the catalytic β subunit, a centerpiece in communication between rotor subunits and catalytic sites, to drive the rotary mechanism. As a model system, we used the F1 sector of Escherichia coli, a bacterium included in the priority list of multidrug-resistant pathogens. Drug-like molecules and an IF1-derived peptide, designed through molecular dynamics simulations and sequence mining approaches, respectively, exhibited in vitro micromolar inhibitor potency against F1. An analysis of bacterial and Mammalia sequences of the key structural helix-turn-turn motif of the C-terminal domain of the β subunit revealed highly and moderately conserved positions that could be exploited for the development of new species-specific allosteric inhibitors. To our knowledge, these inhibitors are the first binders computationally designed against the catalytic subunit of FOF1-ATP synthase. |
Macarena Corro-Morón Albert Granell, Varbina Ivanova Elena Domingo Raúl Beltrán-Debón Xavier Barril Maria-Jesus Sanz Isabel Matheu Sergio Castillón Yolanda Díaz Bioorganic Chemistry, 2022. @article{Corro-Morón2022, title = {Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition}, author = {Macarena Corro-Morón, Albert Granell, Varbina Ivanova, Elena Domingo, Raúl Beltrán-Debón, Xavier Barril, Maria-Jesus Sanz, M Isabel Matheu, Sergio Castillón, Yolanda Díaz}, url = {https://doi.org/10.1016/j.bioorg.2022.105668}, doi = {10.1016/j.bioorg.2022.105668}, year = {2022}, date = {2022-04-01}, journal = {Bioorganic Chemistry}, abstract = {Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 μM.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 μM. |
Daniel Alvarez-Garcia Peter Schmidtke, Elena Cubero Xavier Barril Current Drug Discovery Technologies, 2022. @article{Alvarez-Garcia2022, title = {Extracting Atomic Contributions to Binding Free Energy Using Molecular Dynamics Simulations with Mixed Solvents (MDmix)}, author = {Daniel Alvarez-Garcia, Peter Schmidtke, Elena Cubero, Xavier Barril}, url = {https://doi.org/10.2174/1570163819666211223162829}, doi = {10.2174/1570163819666211223162829}, year = {2022}, date = {2022-03-01}, journal = {Current Drug Discovery Technologies}, abstract = {Mixed solvents MD (MDmix) simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery. One of the assumptions behind the methodology is the transferability of free energy values from the simulated cosolvent molecules to larger drug-like molecules. However, the binding free energy maps (ΔGbind) calculated for the different moieties of the cosolvent molecules (e.g. a hydroxyl map for the ethanol) are largely influenced by the rest of the solvent molecule and do not reflect the intrinsic affinity of the moiety in question. As such, they are hardly transferable to different molecules.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Mixed solvents MD (MDmix) simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery. One of the assumptions behind the methodology is the transferability of free energy values from the simulated cosolvent molecules to larger drug-like molecules. However, the binding free energy maps (ΔGbind) calculated for the different moieties of the cosolvent molecules (e.g. a hydroxyl map for the ethanol) are largely influenced by the rest of the solvent molecule and do not reflect the intrinsic affinity of the moiety in question. As such, they are hardly transferable to different molecules. |
Piticchio, Serena; Martínez-Cartró, Míriam; Scaffidi, Salvatore; Rachman, Moira; Rodriguez-Arevalo, Sergio; Sanchez-Arfelis, Ainoa; Escolano, Carmen; Picaud, Sarah; Krojer, Tobias; Filippakopoulos, Panagis; von Delft, Frank; Galdeano, Carles; Barril, Xavier Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space Journal of Medicinal Chemistry, 2021. @article{Serena_2021, title = {Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space}, author = {Piticchio, Serena G. and Martínez-Cartró, Míriam and Scaffidi, Salvatore and Rachman, Moira and Rodriguez-Arevalo, Sergio and Sanchez-Arfelis, Ainoa and Escolano, Carmen and Picaud, Sarah and Krojer, Tobias and Filippakopoulos, Panagis and von Delft, Frank and Galdeano, Carles and Barril, Xavier}, url = {https://doi.org/10.1021/acs.jmedchem.1c01108}, doi = {10.1021/acs.jmedchem.1c01108}, year = {2021}, date = {2021-12-13}, journal = {Journal of Medicinal Chemistry}, abstract = {Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD. |
Rachman, Moira; Piticchio, Serena; Majewski, Maciej; Barril, Xavier Fragment-to-lead tailored in silico design Drug Discovery Today: Technologies, pp. 1740-6749, 2021. @article{Rachman2021, title = {Fragment-to-lead tailored in silico design}, author = {Rachman, Moira and Piticchio, Serena and Majewski, Maciej and Barril, Xavier}, url = {https://www.sciencedirect.com/science/article/pii/S1740674921000226}, doi = {https://doi.org/10.1016/j.ddtec.2021.08.005}, year = {2021}, date = {2021-09-03}, journal = {Drug Discovery Today: Technologies}, pages = {1740-6749}, abstract = {Fragment-based drug discovery (FBDD) emerged as a disruptive technology and became established during the last two decades. Its rationality and low entry costs make it appealing, and the numerous examples of approved drugs discovered through FBDD validate the approach. However, FBDD still faces numerous challenges. Perhaps the most important one is the transformation of the initial fragment hits into viable leads. Fragment-to-lead (F2L) optimization is resource-intensive and is therefore limited in the possibilities that can be actively pursued. In silico strategies play an important role in F2L, as they can perform a deeper exploration of chemical space, prioritize molecules with high probabilities of being active and generate non-obvious ideas. Here we provide a critical overview of current in silico strategies in F2L optimization and highlight their remarkable impact. While very effective, most solutions are target- or fragment- specific. We propose that fully integrated in silico strategies, capable of automatically and systematically exploring the fast-growing available chemical space can have a significant impact on accelerating the release of fragment originated drugs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fragment-based drug discovery (FBDD) emerged as a disruptive technology and became established during the last two decades. Its rationality and low entry costs make it appealing, and the numerous examples of approved drugs discovered through FBDD validate the approach. However, FBDD still faces numerous challenges. Perhaps the most important one is the transformation of the initial fragment hits into viable leads. Fragment-to-lead (F2L) optimization is resource-intensive and is therefore limited in the possibilities that can be actively pursued. In silico strategies play an important role in F2L, as they can perform a deeper exploration of chemical space, prioritize molecules with high probabilities of being active and generate non-obvious ideas. Here we provide a critical overview of current in silico strategies in F2L optimization and highlight their remarkable impact. While very effective, most solutions are target- or fragment- specific. We propose that fully integrated in silico strategies, capable of automatically and systematically exploring the fast-growing available chemical space can have a significant impact on accelerating the release of fragment originated drugs. |
Barril, Dylan Serillon; Carles Bo; Xavier Testing automatic methods to predict free binding energy of host–guest complexes in SAMPL7 challenge Journal of Computer-Aided Molecular Design , (35), pp. 209-222, 2021. @article{Dylan2021, title = {Testing automatic methods to predict free binding energy of host–guest complexes in SAMPL7 challenge}, author = {Dylan Serillon; Carles Bo; Xavier Barril }, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904704/pdf/10822_2020_Article_370.pdf}, doi = {https://doi.org/10.1007/s10822-020-00370-6}, year = {2021}, date = {2021-02-19}, journal = {Journal of Computer-Aided Molecular Design }, number = {35}, pages = {209-222}, abstract = {The design of new host–guest complexes represents a fundamental challenge in supramolecular chemistry. At the same time, it opens new opportunities in material sciences or biotechnological applications. A computational tool capable of automati-cally predicting the binding free energy of any host–guest complex would be a great aid in the design of new host systems, or to identify new guest molecules for a given host. We aim to build such a platform and have used the SAMPL7 challenge to test several methods and design a specific computational pipeline. Predictions will be based on machine learning (when previous knowledge is available) or a physics-based method (otherwise). The formerly delivered predictions with an RMSE of 1.67 kcal/mol but will require further work to identify when a specific system is outside of the scope of the model. The latter is combines the semiempirical GFN2B functional, with docking, molecular mechanics, and molecular dynamics. Correct predictions (RMSE of 1.45 kcal/mol) are contingent on the identification of the correct binding mode, which can be very challenging for host–guest systems with a large number of degrees of freedom. Participation in the blind SAMPL7 challenge provided fundamental direction to the project. More advanced versions of the pipeline will be tested against future SAMPL challenges.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The design of new host–guest complexes represents a fundamental challenge in supramolecular chemistry. At the same time, it opens new opportunities in material sciences or biotechnological applications. A computational tool capable of automati-cally predicting the binding free energy of any host–guest complex would be a great aid in the design of new host systems, or to identify new guest molecules for a given host. We aim to build such a platform and have used the SAMPL7 challenge to test several methods and design a specific computational pipeline. Predictions will be based on machine learning (when previous knowledge is available) or a physics-based method (otherwise). The formerly delivered predictions with an RMSE of 1.67 kcal/mol but will require further work to identify when a specific system is outside of the scope of the model. The latter is combines the semiempirical GFN2B functional, with docking, molecular mechanics, and molecular dynamics. Correct predictions (RMSE of 1.45 kcal/mol) are contingent on the identification of the correct binding mode, which can be very challenging for host–guest systems with a large number of degrees of freedom. Participation in the blind SAMPL7 challenge provided fundamental direction to the project. More advanced versions of the pipeline will be tested against future SAMPL challenges. |
C Galdeano, Barril Targeted Protein Degradation Chemical Probes 2020. @inbook{Galdeano2020, title = {Targeted Protein Degradation Chemical Probes}, author = {C Galdeano, X Barril}, url = {DOI https://doi.org/10.1039/9781839160745-00150}, doi = {10.1039/9781839160745-00150}, year = {2020}, date = {2020-11-17}, journal = {The Discovery and Utility of Chemical Probes in Target Discovery}, abstract = {During normal cellular homeostasis, proteins are constantly synthesized and destroyed. The ubiquitin–proteasome system (UPS) pathway is ultimately responsible for the controlled degradation of 80% of the proteome via ubiquitination. Protein ubiquitination occurs through a highly organized and orchestrated cascade of enzymatic reactions, involving an E1 ubiquitinactivating enzyme, an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin–-ligase complex that covalently binds ubiquitin to the side chain of a lysine. 1 Repeated iterations of this ubiquitination process result in long chains of ubiquitin in a given target protein and its posterior degradation by the 26S proteasome. The therapeutic and biological potential of intervention in the UPS was demonstrated by proteasome inhibitors such as peptide boronic acids (bortezomib) and epoxyketones (carfilzomib), which have had success.}, keywords = {}, pubstate = {published}, tppubtype = {inbook} } During normal cellular homeostasis, proteins are constantly synthesized and destroyed. The ubiquitin–proteasome system (UPS) pathway is ultimately responsible for the controlled degradation of 80% of the proteome via ubiquitination. Protein ubiquitination occurs through a highly organized and orchestrated cascade of enzymatic reactions, involving an E1 ubiquitinactivating enzyme, an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin–-ligase complex that covalently binds ubiquitin to the side chain of a lysine. 1 Repeated iterations of this ubiquitination process result in long chains of ubiquitin in a given target protein and its posterior degradation by the 26S proteasome. The therapeutic and biological potential of intervention in the UPS was demonstrated by proteasome inhibitors such as peptide boronic acids (bortezomib) and epoxyketones (carfilzomib), which have had success. |
Rachman, Moira; Bajusz, Dávid; Hetényi, Anasztázia; Scarpino, Andrea; Merő, Balázs; Egyed, Attila; Buday, László; Barril, Xavier; Keserű, György Discovery of a novel kinase hinge binder fragment by dynamic undocking RSC Med. Chem., 2020. @article{C9MD00519F, title = {Discovery of a novel kinase hinge binder fragment by dynamic undocking}, author = {Rachman, Moira and Bajusz, Dávid and Hetényi, Anasztázia and Scarpino, Andrea and Merő, Balázs and Egyed, Attila and Buday, László and Barril, Xavier and Keserű, György M.}, url = {http://dx.doi.org/10.1039/C9MD00519F}, doi = {10.1039/C9MD00519F}, year = {2020}, date = {2020-03-04}, journal = {RSC Med. Chem.}, publisher = {RSC}, abstract = {One of the key motifs of type I kinase inhibitors is their interactions with the hinge region of ATP binding sites. These interactions contribute significantly to the potency of the inhibitors; however, only a tiny fraction of the available chemical space has been explored with kinase inhibitors reported in the last twenty years. This paper describes a workflow utilizing docking with rDock and dynamic undocking (DUck) for the virtual screening of fragment libraries in order to identify fragments that bind to the kinase hinge region. We have identified 8-amino-2H-isoquinolin-1-one (MR1), a novel and potent hinge binding fragment, which was experimentally tested on a diverse set of kinases, and is hereby suggested for future fragment growing or merging efforts against various kinases, particularly MELK. Direct binding of MR1 to MELK was confirmed by STD-NMR, and its binding to the ATP-pocket was confirmed by a new competitive binding assay based on microscale thermophoresis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } One of the key motifs of type I kinase inhibitors is their interactions with the hinge region of ATP binding sites. These interactions contribute significantly to the potency of the inhibitors; however, only a tiny fraction of the available chemical space has been explored with kinase inhibitors reported in the last twenty years. This paper describes a workflow utilizing docking with rDock and dynamic undocking (DUck) for the virtual screening of fragment libraries in order to identify fragments that bind to the kinase hinge region. We have identified 8-amino-2H-isoquinolin-1-one (MR1), a novel and potent hinge binding fragment, which was experimentally tested on a diverse set of kinases, and is hereby suggested for future fragment growing or merging efforts against various kinases, particularly MELK. Direct binding of MR1 to MELK was confirmed by STD-NMR, and its binding to the ATP-pocket was confirmed by a new competitive binding assay based on microscale thermophoresis. |
Majewski, Maciej; Barril, Xavier Structural Stability Predicts the Binding Mode of Protein–Ligand Complexes Journal of Chemical Information and Modeling, 0 (0), pp. null, 2020, (PMID: 32052965). @article{Maciej2020, title = {Structural Stability Predicts the Binding Mode of Protein–Ligand Complexes}, author = {Majewski, Maciej and Barril, Xavier}, url = {https://doi.org/10.1021/acs.jcim.9b01062}, doi = {10.1021/acs.jcim.9b01062}, year = {2020}, date = {2020-02-29}, journal = {Journal of Chemical Information and Modeling}, volume = {0}, number = {0}, pages = {null}, abstract = {The prediction of a ligand’s binding mode into its macromolecular target is essential in structure-based drug discovery. Even though tremendous effort has been made to address this problem, most of the developed tools work similarly, trying to predict the binding free energy associated with each particular binding mode. In this study, we decided to abandon this criterion, following structural stability instead. This view, implemented in a novel computational workflow, quantifies the steepness of the local energy minimum associated with each potential binding mode. Surprisingly, the protocol outperforms docking scoring functions in case of fragments (ligands with MW < 300 Da) and is as good as docking for drug-like molecules. It also identifies substructures that act as structural anchors, predicting their binding mode with particular accuracy. The results open a new physical perspective for binding mode prediction, which can be combined with existing thermodynamic-based approaches.}, note = {PMID: 32052965}, keywords = {}, pubstate = {published}, tppubtype = {article} } The prediction of a ligand’s binding mode into its macromolecular target is essential in structure-based drug discovery. Even though tremendous effort has been made to address this problem, most of the developed tools work similarly, trying to predict the binding free energy associated with each particular binding mode. In this study, we decided to abandon this criterion, following structural stability instead. This view, implemented in a novel computational workflow, quantifies the steepness of the local energy minimum associated with each potential binding mode. Surprisingly, the protocol outperforms docking scoring functions in case of fragments (ligands with MW < 300 Da) and is as good as docking for drug-like molecules. It also identifies substructures that act as structural anchors, predicting their binding mode with particular accuracy. The results open a new physical perspective for binding mode prediction, which can be combined with existing thermodynamic-based approaches. |
Estarellas, Carolina; Scaffidi, Salvatore; Saladino, Giorgio; Spyrakis, Francesca; Franzoni, Lorella; Galdeano, Carles; Bidon-Chanal, Axel; Gervasio, Francesco Luigi; Luque, Javier The journal of Physical Chemistry Letters, 2019. @article{Estarellas2019, title = {Modulating Ligand Dissociation Through Methyl Isomerism in Accessory Sites: Binding of Retinol to Cellular Carriers}, author = {Carolina Estarellas and Salvatore Scaffidi and Giorgio Saladino and Francesca Spyrakis and Lorella Franzoni and Carles Galdeano and Axel Bidon-Chanal and Francesco Luigi Gervasio and F. Javier Luque}, url = {https://pubs.acs.org/doi/10.1021/acs.jpclett.9b02861}, doi = {10.1021/acs.jpclett.9b02861}, year = {2019}, date = {2019-11-12}, journal = {The journal of Physical Chemistry Letters}, abstract = {Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled at large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that a fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled at large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that a fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites. |
Majewski, Maciej; Ruiz-Carmona, Sergio; Barril, Xavier Communications Chemistry, 2 ( 110), 2019, ISSN: 2399-3669. @article{Maciej2019, title = {An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder}, author = {Maciej Majewski and Sergio Ruiz-Carmona and Xavier Barril }, url = {https://doi.org/10.1038/s42004-019-0205-5}, doi = {10.1038/s42004-019-0205-5}, issn = {2399-3669}, year = {2019}, date = {2019-09-17}, journal = {Communications Chemistry}, volume = {2}, number = { 110}, abstract = {The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 drug-like and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 drug-like and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design. |
Rachman Moira; Scarpino, Andrea; Bajusz Dávid; Pálfy Gyula; Vida István; Perczel András; Barril Xavier; Keserű György DUckCov: a Dynamic Undocking-Based Virtual Screening Protocol for Covalent Binders ChemMedChem, 2019, (PMID: 30786178). @article{Rachman2019, title = {DUckCov: a Dynamic Undocking-Based Virtual Screening Protocol for Covalent Binders}, author = {Rachman, Moira; Scarpino, Andrea; Bajusz, Dávid; Pálfy, Gyula; Vida, István; Perczel, András; Barril, Xavier; Keserű, György M. }, url = {https://doi.org/10.1002/cmdc.201900078}, doi = { 10.1002/cmdc.201900078}, year = {2019}, date = {2019-02-20}, journal = {ChemMedChem}, abstract = {Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non-conserved nucleophilic residues, optimizing the noncovalent binding framework is important to improve potency and selectivity of covalent binders toward the desired target. Significant efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode prediction. To highlight the value of the noncovalent complex in the covalent binding process, here we describe a new protocol using tethered and constrained docking in combination with Dynamic Undocking (DUck) as a tool to privilege strong protein binders for the identification of novel covalent inhibitors. At the end of the protocol, dedicated covalent docking methods were used to rank and select the virtual hits based on the predicted binding mode. By validating the method on JAK3 and KRas, we demonstrate how this fast iterative protocol can be applied to explore a wide chemical space and identify potent targeted covalent inhibitors.}, note = {PMID: 30786178}, keywords = {}, pubstate = {published}, tppubtype = {article} } Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non-conserved nucleophilic residues, optimizing the noncovalent binding framework is important to improve potency and selectivity of covalent binders toward the desired target. Significant efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode prediction. To highlight the value of the noncovalent complex in the covalent binding process, here we describe a new protocol using tethered and constrained docking in combination with Dynamic Undocking (DUck) as a tool to privilege strong protein binders for the identification of novel covalent inhibitors. At the end of the protocol, dedicated covalent docking methods were used to rank and select the virtual hits based on the predicted binding mode. By validating the method on JAK3 and KRas, we demonstrate how this fast iterative protocol can be applied to explore a wide chemical space and identify potent targeted covalent inhibitors. |
Rachman Moira; Barril, Xavier; Hubbard Roderick Predicting how drug molecules bind to their protein targets. Current Opinion in Pharmacology, 42 , pp. 34-39, 2018, ISSN: 1471-4892. @article{Rachman2018, title = {Predicting how drug molecules bind to their protein targets.}, author = {Rachman, Moira; Barril, Xavier; Hubbard, Roderick E.}, url = {http://www.sciencedirect.com/science/article/pii/S1471489218300249}, doi = {https://doi.org/10.1016/j.coph.2018.07.001}, issn = {1471-4892}, year = {2018}, date = {2018-10-01}, journal = {Current Opinion in Pharmacology}, volume = {42}, pages = {34-39}, abstract = {There have been substantial advances in the application of molecular modelling and simulation to drug discovery in recent years, as massive increases in computer power are coupled with continued development in the underlying methods and understanding of how to apply them. Here, we survey recent advances in one particular area—predicting how a known ligand binds to a particular protein. We focus on the four contributing classes of calculation: predicting where a binding site is on a protein; characterizing where chemical functional groups will bind to that site; molecular docking to generate a binding mode for a ligand and dynamics simulations to refine that pose and allow for protein conformation change. Examples of successful application are provided for each class.}, keywords = {}, pubstate = {published}, tppubtype = {article} } There have been substantial advances in the application of molecular modelling and simulation to drug discovery in recent years, as massive increases in computer power are coupled with continued development in the underlying methods and understanding of how to apply them. Here, we survey recent advances in one particular area—predicting how a known ligand binds to a particular protein. We focus on the four contributing classes of calculation: predicting where a binding site is on a protein; characterizing where chemical functional groups will bind to that site; molecular docking to generate a binding mode for a ligand and dynamics simulations to refine that pose and allow for protein conformation change. Examples of successful application are provided for each class. |
Barril, Xavier Computer-aided drug design: time to play with novel chemical matter Expert Opinion on Drug Discovery, 12 (10), pp. 977-980, 2017, (PMID: 28756685). @article{doi:10.1080/17460441.2017.1362386, title = {Computer-aided drug design: time to play with novel chemical matter}, author = {Xavier Barril}, url = {http://dx.doi.org/10.1080/17460441.2017.1362386}, doi = {10.1080/17460441.2017.1362386}, year = {2017}, date = {2017-08-03}, journal = {Expert Opinion on Drug Discovery}, volume = {12}, number = {10}, pages = {977-980}, publisher = {Taylor & Francis}, note = {PMID: 28756685}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Westermaier Yvonne; Ruiz-Carmona, Sergio; Theret Isabelle; Perron-Sierra Françoise; Poissonnet Guillaume; Dacquet Catherine; Boutin Jean Ducrot Pierre; Barril Xavier Binding mode prediction and MD/MMPBSA-based free energy ranking for agonists of REV-ERBα/NCoR Journal of Computer-Aided Molecular Design, 2017, ISSN: 1573-4951. @article{Westermaier2017, title = {Binding mode prediction and MD/MMPBSA-based free energy ranking for agonists of REV-ERBα/NCoR}, author = {Westermaier, Yvonne; Ruiz-Carmona, Sergio; Theret, Isabelle; Perron-Sierra, Françoise; Poissonnet, Guillaume; Dacquet, Catherine; Boutin, Jean A.; Ducrot, Pierre; Barril, Xavier}, url = {https://doi.org/10.1007/s10822-017-0040-7}, doi = {10.1007/s10822-017-0040-7}, issn = {1573-4951}, year = {2017}, date = {2017-07-15}, journal = {Journal of Computer-Aided Molecular Design}, abstract = {The knowledge of the free energy of binding of small molecules to a macromolecular target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a molecular dynamics (MD)-based approach can be used to predict the free energy of small molecules, and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERB$alpha$ with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines molecular docking, molecular dynamics (MD), solvent-accessible surface area (SASA) and molecular mechanics poisson boltzmann surface area (MMPBSA) calculations. While docking yielded initial hints on the binding modes, their stability was assessed by MD. The SASA calculations revealed that the presence of the ligand led to a higher exposure of hydrophobic REV-ERB residues for NCoR recruitment. MMPBSA was very successful in ranking ligands by potency in a retrospective and prospective manner. Particularly, the prospective MMPBSA ranking-based validations for four compounds, three predicted to be active and one weakly active, were confirmed experimentally.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The knowledge of the free energy of binding of small molecules to a macromolecular target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a molecular dynamics (MD)-based approach can be used to predict the free energy of small molecules, and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERB$alpha$ with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines molecular docking, molecular dynamics (MD), solvent-accessible surface area (SASA) and molecular mechanics poisson boltzmann surface area (MMPBSA) calculations. While docking yielded initial hints on the binding modes, their stability was assessed by MD. The SASA calculations revealed that the presence of the ligand led to a higher exposure of hydrophobic REV-ERB residues for NCoR recruitment. MMPBSA was very successful in ranking ligands by potency in a retrospective and prospective manner. Particularly, the prospective MMPBSA ranking-based validations for four compounds, three predicted to be active and one weakly active, were confirmed experimentally. |
Radusky Leandro; Ruiz-Carmona, Sergi; Modenutti Carlo; Barril Xavier; Turjanski Adrian Martí Marcelo LigQ: A Webserver to Select and Prepare Ligands for Virtual Screening Journal of Chemical Information and Modeling, 0 (0), 2017, (PMID: 28700230). @article{doi:10.1021/acs.jcim.7b00241b, title = {LigQ: A Webserver to Select and Prepare Ligands for Virtual Screening}, author = {Radusky, Leandro; Ruiz-Carmona, Sergi; Modenutti, Carlo; Barril, Xavier; Turjanski, Adrian G.; Martí, Marcelo A.}, url = {http://dx.doi.org/10.1021/acs.jcim.7b00241}, doi = {10.1021/acs.jcim.7b00241}, year = {2017}, date = {2017-07-12}, journal = {Journal of Chemical Information and Modeling}, volume = {0}, number = {0}, note = {PMID: 28700230}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Arcon Juan Pablo; Defelipe, Lucas Alfredo; Modenutti Carlos Pablo; Lopez Elias Daniel; Alvarez-Garcia Daniel; Barril Xavier; Turjanski Adrian Gustavo; Marti, Marcelo Journal of Chemical Information and Modeling, AOP , 2017, ISSN: 1549-9596. @article{Arcon2017, title = {Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking and Allows Accurate Binding Free Energy Predictions}, author = {Arcon, Juan Pablo; Defelipe, Lucas A Alfredo; Modenutti, Carlos Pablo; Lopez, Elias Daniel; Alvarez-Garcia, Daniel; Barril, Xavier; Turjanski, Adrian Gustavo and Marti, Marcelo A. }, url = {http://dx.doi.org/10.1021/acs.jcim.6b00678}, doi = {10.1021/acs.jcim.6b00678}, issn = {1549-9596}, year = {2017}, date = {2017-03-20}, journal = {Journal of Chemical Information and Modeling}, volume = {AOP}, abstract = {One of the most important biological processes at the molecular level is the formation of proteinligand complexes. Therefore, determining their structure and underlying key interactions is of paramount relevance and has direct applications in drug development. Due to its low cost relative to its experimental sibling, Molecular Dynamics (MD) simulations in the presence of different solvent probes mimicking specific type of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots. However, a systematic comparison of different probes and their real predictive power from a quantitative and thermodynamic point of view is still missing. In the present work we have performed MD simulations of 18 different proteins in pure water as well as water mixtures of ethanol, acetamide, acetonitrile and methylammonium acetate, leading to a total of 5.4 microseconds simulation time. For each system we determined the corresponding solvent sites, defined as space regions adjacent to the protein surface where the probability of finding a probe atom is higher than that in the bulk solvent. Finally, we compared the identified solvent sites with 121 different protein-ligand complexes and used them to perform molecular docking and ligand binding free energy estimates. Our results show that combining solely water and ethanol sites allows sampling over 70% of all possible protein-ligand interactions, especially those that coincide with ligand-based pharmacophoric points. Most important, we also show how the solvent sites can be used to significantly improve ligand docking in terms of both accuracy and precision, and that accurate predictions of ligand binding free energies, along with relative ranking of ligand affinity, can be performed. }, keywords = {}, pubstate = {published}, tppubtype = {article} } One of the most important biological processes at the molecular level is the formation of proteinligand complexes. Therefore, determining their structure and underlying key interactions is of paramount relevance and has direct applications in drug development. Due to its low cost relative to its experimental sibling, Molecular Dynamics (MD) simulations in the presence of different solvent probes mimicking specific type of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots. However, a systematic comparison of different probes and their real predictive power from a quantitative and thermodynamic point of view is still missing. In the present work we have performed MD simulations of 18 different proteins in pure water as well as water mixtures of ethanol, acetamide, acetonitrile and methylammonium acetate, leading to a total of 5.4 microseconds simulation time. For each system we determined the corresponding solvent sites, defined as space regions adjacent to the protein surface where the probability of finding a probe atom is higher than that in the bulk solvent. Finally, we compared the identified solvent sites with 121 different protein-ligand complexes and used them to perform molecular docking and ligand binding free energy estimates. Our results show that combining solely water and ethanol sites allows sampling over 70% of all possible protein-ligand interactions, especially those that coincide with ligand-based pharmacophoric points. Most important, we also show how the solvent sites can be used to significantly improve ligand docking in terms of both accuracy and precision, and that accurate predictions of ligand binding free energies, along with relative ranking of ligand affinity, can be performed. |
Galdeano, Carles Drugging the undruggable: targeting challenging E3 ligases for personalized medicine Future Medicinal Chemistry, 9 (4), pp. 347-350, 2017, ISSN: 1756-8919. @article{Galdeano2017, title = {Drugging the undruggable: targeting challenging E3 ligases for personalized medicine}, author = {Galdeano, Carles}, url = {http://www.future-science.com/doi/10.4155/fmc-2017-0009}, doi = {10.4155/fmc-2017-0009}, issn = {1756-8919}, year = {2017}, date = {2017-03-06}, journal = {Future Medicinal Chemistry}, volume = {9}, number = {4}, pages = {347-350}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Arimany-Nardi Cristina; Claudio-Montero, Ana Maria; Viel-Oliva Albert; Schmidtke Peter; Estarellas Carolina; Barril Xavier; Bidon-Chanal Axel; Pastor-Anglada Marçal Molecular Pharmaceutics, 14 (6), pp. 1980-1987, 2017, (PMID: 28441873). @article{doi:10.1021/acs.molpharmaceut.7b00085, title = {Identification and Characterization of a Secondary Sodium-Binding Site and the Main Selectivity Determinants in the Human Concentrative Nucleoside Transporter 3}, author = {Arimany-Nardi, Cristina; Claudio-Montero, Ana Maria; Viel-Oliva, Albert; Schmidtke, Peter; Estarellas, Carolina; Barril, Xavier; Bidon-Chanal, Axel; Pastor-Anglada, Marçal}, url = {http://dx.doi.org/10.1021/acs.molpharmaceut.7b00085}, doi = {10.1021/acs.molpharmaceut.7b00085}, year = {2017}, date = {2017-01-01}, journal = {Molecular Pharmaceutics}, volume = {14}, number = {6}, pages = {1980-1987}, note = {PMID: 28441873}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Duran-Frigola, Miquel; Siragusa, Lydia; Ruppin, Eytan; Barril, Xavier; Cruciani, Gabriele; Aloy, Patrick Detecting similar binding pockets to enable systems polypharmacology PLOS Computational Biology, 13 (6), pp. 1-18, 2017. @article{10.1371/journal.pcbi.1005522, title = {Detecting similar binding pockets to enable systems polypharmacology}, author = {Duran-Frigola, Miquel AND Siragusa, Lydia AND Ruppin, Eytan AND Barril, Xavier AND Cruciani, Gabriele AND Aloy, Patrick}, url = {https://doi.org/10.1371/journal.pcbi.1005522}, doi = {10.1371/journal.pcbi.1005522}, year = {2017}, date = {2017-01-01}, journal = {PLOS Computational Biology}, volume = {13}, number = {6}, pages = {1-18}, publisher = {Public Library of Science}, abstract = {Author summary Traditionally, the fact that most drugs are promiscuous binders has been a major concern in pharmacology, due to the occurrence of undesired off-target clinical events. In the recent years, however, the realization that many diseases are the result of complex biological processes has encouraged rethinking of drug promiscuity as a promising feature, since it is sometimes necessary to interfere with multiple receptors in order to overcome the robustness of disease-related networks. One way to identify groups of proteins that could be targeted simultaneously is to look for similar binding sites. We have massively done so for all human proteins with a known high-resolution three-dimensional structure, unveiling a vast space of ‘polypharmacology’ opportunities. Of these, we know, a great majority is not of therapeutic interest. To pinpoint promising multi-target combinations, we advocate for the use of computational tools that are able to rapidly simulate the effect of drug-target interactions on biological networks.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Author summary Traditionally, the fact that most drugs are promiscuous binders has been a major concern in pharmacology, due to the occurrence of undesired off-target clinical events. In the recent years, however, the realization that many diseases are the result of complex biological processes has encouraged rethinking of drug promiscuity as a promising feature, since it is sometimes necessary to interfere with multiple receptors in order to overcome the robustness of disease-related networks. One way to identify groups of proteins that could be targeted simultaneously is to look for similar binding sites. We have massively done so for all human proteins with a known high-resolution three-dimensional structure, unveiling a vast space of ‘polypharmacology’ opportunities. Of these, we know, a great majority is not of therapeutic interest. To pinpoint promising multi-target combinations, we advocate for the use of computational tools that are able to rapidly simulate the effect of drug-target interactions on biological networks. |
Ruiz-Carmona, Sergio; Schmidtke, Peter; Luque, Javier; Baker, Lisa; Matassova, Natalia; Davis, Ben; Roughley, Stephen; Murray, James; Hubbard, Rod; Barril, Xavier Dynamic undocking and the quasi-bound state as tools for drug discovery Nature Chemistry, 9 (3), pp. 201–206 , 2016, ISSN: 1755-4349, (Link to tutorial: www.ub.edu/bl/undocking). @article{RuizDuck2016, title = { Dynamic undocking and the quasi-bound state as tools for drug discovery}, author = {Sergio Ruiz-Carmona and Peter Schmidtke and F. Javier Luque and Lisa Baker and Natalia Matassova and Ben Davis and Stephen Roughley and James Murray and Rod Hubbard and Xavier Barril}, url = {http://dx.doi.org/10.1038/nchem.2660}, issn = {1755-4349}, year = {2016}, date = {2016-11-14}, journal = {Nature Chemistry}, volume = {9}, number = {3}, pages = {201–206 }, abstract = {There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%.}, note = {Link to tutorial: www.ub.edu/bl/undocking}, keywords = {}, pubstate = {published}, tppubtype = {article} } There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%. |
Ruiz-Carmona, Sergio; Barril, Xavier Docking-undocking combination applied to the D3R Grand Challenge 2015 Journal of Computer-Aided Molecular Design, 30 (9), pp. 805–815, 2016, ISSN: 1573-4951. @article{Ruiz-Carmona2016, title = {Docking-undocking combination applied to the D3R Grand Challenge 2015}, author = {Ruiz-Carmona, Sergio and Barril, Xavier}, url = {http://dx.doi.org/10.1007/s10822-016-9979-z}, issn = {1573-4951}, year = {2016}, date = {2016-11-01}, journal = {Journal of Computer-Aided Molecular Design}, volume = {30}, number = {9}, pages = {805--815}, abstract = {Novel methods for drug discovery are constantly under development and independent exercises to test and validate them for different goals are extremely useful. The drug discovery data resource (D3R) Grand Challenge 2015 offers an excellent opportunity as an external assessment and validation experiment for Computer-Aided Drug Discovery methods. The challenge comprises two protein targets and prediction tests: binding mode and ligand ranking. We have faced both of them with the same strategy: pharmacophore-guided docking followed by dynamic undocking (a new method tested experimentally here) and, where possible, critical assessment of the results based on pre-existing information. In spite of using methods that are qualitative in nature, our results for binding mode and ligand ranking were amongst the best on Hsp90. Results for MAP4K4 were less positive and we track the different performance across systems to the level of previous knowledge about accessible conformational states. We conclude that docking is quite effective if supplemented by dynamic undocking and empirical information (e.g. binding hot spots, productive protein conformations). This setup is well suited for virtual screening, a frequent application that was not explicitly tested in this edition of the D3R Grand Challenge 2015. Protein flexibility remains as the main cause for hard failures.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Novel methods for drug discovery are constantly under development and independent exercises to test and validate them for different goals are extremely useful. The drug discovery data resource (D3R) Grand Challenge 2015 offers an excellent opportunity as an external assessment and validation experiment for Computer-Aided Drug Discovery methods. The challenge comprises two protein targets and prediction tests: binding mode and ligand ranking. We have faced both of them with the same strategy: pharmacophore-guided docking followed by dynamic undocking (a new method tested experimentally here) and, where possible, critical assessment of the results based on pre-existing information. In spite of using methods that are qualitative in nature, our results for binding mode and ligand ranking were amongst the best on Hsp90. Results for MAP4K4 were less positive and we track the different performance across systems to the level of previous knowledge about accessible conformational states. We conclude that docking is quite effective if supplemented by dynamic undocking and empirical information (e.g. binding hot spots, productive protein conformations). This setup is well suited for virtual screening, a frequent application that was not explicitly tested in this edition of the D3R Grand Challenge 2015. Protein flexibility remains as the main cause for hard failures. |
Hahn-Herrera, Otto; Salcedo, Guillermo; Barril, Xavier; García-Hernández, Enrique Inherent conformational flexibility of F1-ATPase α-subunit Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1857 (9), pp. 1392 - 1402, 2016, ISSN: 0005-2728. @article{HAHNHERRERA20161392, title = {Inherent conformational flexibility of F1-ATPase α-subunit}, author = {Otto Hahn-Herrera and Guillermo Salcedo and Xavier Barril and Enrique García-Hernández}, url = {http://www.sciencedirect.com/science/article/pii/S0005272816303826}, doi = {http://dx.doi.org/10.1016/j.bbabio.2016.04.283}, issn = {0005-2728}, year = {2016}, date = {2016-01-01}, journal = {Biochimica et Biophysica Acta (BBA) - Bioenergetics}, volume = {1857}, number = {9}, pages = {1392 - 1402}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Barril, Xavier; Danielsson, Helena Binding kinetics in drug discovery Drug Discovery Today: Technologies, 17 , pp. 35–36, 2015, ISSN: 17406749. @article{Barril2015, title = {Binding kinetics in drug discovery}, author = { Xavier Barril and Helena Danielsson}, url = {http://dx.doi.org/10.1016/j.ddtec.2015.10.011}, issn = {17406749}, year = {2015}, date = {2015-01-01}, journal = {Drug Discovery Today: Technologies}, volume = {17}, pages = {35--36}, publisher = {Elsevier Ltd}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Bayó-Puxan, Núria; Rodríguez-Mias, Ricard; Goldflam, Michael; Kotev, Martin; Ciudad, Sonia; Hipolito, Christopher; Varese, Monica; Suga, Hiroaki; Campos-Olivas, Ramón; Barril, Xavier; Guallar, Víctor; Teixidó, Meritxell; García, Jesús; Giralt, Ernest ChemMedChem, 2015, ISSN: 18607187. @article{Bayo-Puxan2015, title = {Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor}, author = { Núria Bayó-Puxan and Ricard Rodríguez-Mias and Michael Goldflam and Martin Kotev and Sonia Ciudad and Christopher J. Hipolito and Monica Varese and Hiroaki Suga and Ramón Campos-Olivas and Xavier Barril and Víctor Guallar and Meritxell Teixidó and Jesús García and Ernest Giralt}, url = {http://dx.doi.org/10.1002/cmdc.201500467}, issn = {18607187}, year = {2015}, date = {2015-01-01}, journal = {ChemMedChem}, abstract = {The modulation of protein-protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain-domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF-VEGFR interaction is a typical domain-domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The modulation of protein-protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain-domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF-VEGFR interaction is a typical domain-domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch. |
Estupiñán, Mónica; Álvarez-García, Daniel; Barril, Xavier; Diaz, Pilar; Manresa, Angeles Plos One, 10 (7), pp. e0131462, 2015, ISSN: 1932-6203. @article{Estupinan2015, title = {In Silico/In Vivo Insights into the Functional and Evolutionary Pathway of Pseudomonas aeruginosa Oleate-Diol Synthase. Discovery of a New Bacterial Di-Heme Cytochrome C Peroxidase Subfamily}, author = { Mónica Estupiñán and Daniel Álvarez-García and Xavier Barril and Pilar Diaz and Angeles Manresa}, url = {http://dx.plos.org/10.1371/journal.pone.0131462}, issn = {1932-6203}, year = {2015}, date = {2015-01-01}, journal = {Plos One}, volume = {10}, number = {7}, pages = {e0131462}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Westermaier, Yvonne; Barril, Xavier; Scapozza, Leonardo Virtual screening: An in silico tool for interlacing the chemical universe with the proteome Methods, 71 , pp. 44–57, 2015, ISSN: 10462023. @article{Westermaier2015, title = {Virtual screening: An in silico tool for interlacing the chemical universe with the proteome}, author = { Yvonne Westermaier and Xavier Barril and Leonardo Scapozza}, url = {http://linkinghub.elsevier.com/retrieve/pii/S104620231400259X}, issn = {10462023}, year = {2015}, date = {2015-01-01}, journal = {Methods}, volume = {71}, pages = {44--57}, publisher = {Elsevier Inc.}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Juarez-Jimenez, Jordi; Barril, Xavier; Orozco, Modesto; Pouplana, Ramon; Luque, Javier Journal of Physical Chemistry B, 119 (3), pp. 1164–1172, 2015, ISSN: 15205207. @article{Ju??rez-Jim??nez2015, title = {Assessing the suitability of the multilevel strategy for the conformational analysis of small ligands}, author = { Jordi Juarez-Jimenez and Xavier Barril and Modesto Orozco and Ramon Pouplana and F. Javier Luque}, url = {http://dx.doi.org/10.1021/jp506779y}, issn = {15205207}, year = {2015}, date = {2015-01-01}, journal = {Journal of Physical Chemistry B}, volume = {119}, number = {3}, pages = {1164--1172}, abstract = {Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Furthermore, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Furthermore, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution. |
Barril, Xavier Ligand discovery: Docking points. Nature chemistry, 6 (7), pp. 560–561, 2014, ISSN: 1755-4349. @article{Barril2014, title = {Ligand discovery: Docking points.}, author = { Xavier Barril}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24950321}, issn = {1755-4349}, year = {2014}, date = {2014-06-01}, journal = {Nature chemistry}, volume = {6}, number = {7}, pages = {560--561}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Alvarez-Garcia, Daniel; Barril, Xavier Relationship between Protein Flexibility and Binding: Lessons for Structure-Based Drug Design Journal of Chemical Theory and Computation, 10 (6), pp. 2608–2614, 2014, ISSN: 1549-9618. @article{Alvarez-Garcia2014jctc, title = {Relationship between Protein Flexibility and Binding: Lessons for Structure-Based Drug Design}, author = { Daniel Alvarez-Garcia and Xavier Barril}, url = {http://pubs.acs.org/doi/abs/10.1021/ct500182z}, issn = {1549-9618}, year = {2014}, date = {2014-06-01}, journal = {Journal of Chemical Theory and Computation}, volume = {10}, number = {6}, pages = {2608--2614}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Ruiz-Carmona, Sergio; Alvarez-Garcia, Daniel; Foloppe, Nicolas; a. Garmendia-Doval, Beatriz; Juhos, Szilveszter; Schmidtke, Peter; Barril, Xavier; Hubbard, Roderick; Morley, David rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids PLoS Computational Biology, 10 (4), pp. e1003571, 2014, ISSN: 1553-7358. @article{Ruiz-Carmona2014, title = {rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids}, author = { Sergio Ruiz-Carmona and Daniel Alvarez-Garcia and Nicolas Foloppe and a. Beatriz Garmendia-Doval and Szilveszter Juhos and Peter Schmidtke and Xavier Barril and Roderick E. Hubbard and S. David Morley}, editor = {Prlic, Andreas}, url = {http://dx.plos.org/10.1371/journal.pcbi.1003571}, issn = {1553-7358}, year = {2014}, date = {2014-04-01}, journal = {PLoS Computational Biology}, volume = {10}, number = {4}, pages = {e1003571}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Aguilar, Helena; Urruticoechea, Ander; Halonen, Pasi; Kiyotani, Kazuma; Mushiroda, Taisei; Barril, Xavier; Serra-Musach, Jordi; Islam, Abul; Caizzi, Livia; Croce, Luciano Di; Nevedomskaya, Ekaterina; Zwart, Wilbert; Bostner, Josefine; Karlsson, Elin; Tenorio, Gizeh Pérez; Fornander, Tommy; Sgroi, Dennis; Garcia-Mata, Rafael; Jansen, Maurice; García, Nadia; Bonifaci, Núria; Climent, Fina; Soler, María Teresa; Rodríguez-Vida, Alejo; Gil, Miguel; Brunet, Joan; Martrat, Griselda; Gómez-Baldó, Laia; Extremera, Ana; Figueras, Agnes; Balart, Josep; Clarke, Robert; Burnstein, Kerry; Carlson, Kathryn; Katzenellenbogen, John; Vizoso, Miguel; Esteller, Manel; Villanueva, Alberto; Rodríguez-Peña, Ana; Bustelo, Xosé; Nakamura, Yusuke; Zembutsu, Hitoshi; Staal, Olle; Beijersbergen, Roderick; Pujana, Miguel Angel VAV3 mediates resistance to breast cancer endocrine therapy. Breast cancer research : BCR, 16 (3), pp. R53, 2014, ISSN: 1465-542X. @article{Aguilar2014, title = {VAV3 mediates resistance to breast cancer endocrine therapy.}, author = { Helena Aguilar and Ander Urruticoechea and Pasi Halonen and Kazuma Kiyotani and Taisei Mushiroda and Xavier Barril and Jordi Serra-Musach and Abul Islam and Livia Caizzi and Luciano Di Croce and Ekaterina Nevedomskaya and Wilbert Zwart and Josefine Bostner and Elin Karlsson and Gizeh Pérez Tenorio and Tommy Fornander and Dennis C Sgroi and Rafael Garcia-Mata and Maurice P H M Jansen and Nadia García and Núria Bonifaci and Fina Climent and María Teresa Soler and Alejo Rodríguez-Vida and Miguel Gil and Joan Brunet and Griselda Martrat and Laia Gómez-Baldó and Ana I Extremera and Agnes Figueras and Josep Balart and Robert Clarke and Kerry L Burnstein and Kathryn E Carlson and John A Katzenellenbogen and Miguel Vizoso and Manel Esteller and Alberto Villanueva and Ana B Rodríguez-Peña and Xosé R Bustelo and Yusuke Nakamura and Hitoshi Zembutsu and Olle Staal and Roderick L Beijersbergen and Miguel Angel Pujana}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4076632&tool=pmcentrez&rendertype=abstract}, issn = {1465-542X}, year = {2014}, date = {2014-01-01}, journal = {Breast cancer research : BCR}, volume = {16}, number = {3}, pages = {R53}, abstract = {INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor $alpha$ (ER$alpha$) are among the most effective systemic treatments for ER$alpha$-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ER$alpha$ transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.$backslash$n$backslash$nMETHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ER$alpha$ was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.$backslash$n$backslash$nRESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ER$alpha$. VAV3 was selectively reduced upon exposure to YC-1 or ER$alpha$ depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.$backslash$n$backslash$nCONCLUSIONS: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.}, keywords = {}, pubstate = {published}, tppubtype = {article} } INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor $alpha$ (ER$alpha$) are among the most effective systemic treatments for ER$alpha$-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ER$alpha$ transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.$backslash$n$backslash$nMETHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ER$alpha$ was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.$backslash$n$backslash$nRESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ER$alpha$. VAV3 was selectively reduced upon exposure to YC-1 or ER$alpha$ depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.$backslash$n$backslash$nCONCLUSIONS: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer. |
Álvarez-García, Daniel; Barril, Xavier Journal of Medicinal Chemistry, (57), 2014. @article{Alvarez-Garcia2014jmc, title = {Molecular Simulations with Solvent Competition Quantify Water Displaceability and Provide Accurate Interaction Maps of Protein Binding Sites}, author = { Daniel Álvarez-García and Xavier Barril}, url = {http://pubs.acs.org/doi/abs/10.1021/jm5010418}, year = {2014}, date = {2014-01-01}, journal = {Journal of Medicinal Chemistry}, number = {57}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Radusky, Leandro; Defelipe, Lucas; Lanzarotti, Esteban; Luque, Javier; Barril, Xavier; Marti, Marcelo; Turjanski, Adrián TuberQ: a Mycobacterium tuberculosis protein druggability database. Database : the journal of biological databases and curation, 2014 , pp. 1–10, 2014, ISSN: 17580463. @article{Radusky2014, title = {TuberQ: a Mycobacterium tuberculosis protein druggability database.}, author = { Leandro Radusky and Lucas A. Defelipe and Esteban Lanzarotti and Javier Luque and Xavier Barril and Marcelo A. Marti and Adrián G. Turjanski}, url = {http://dx.doi.org/10.1093/database/bau035}, issn = {17580463}, year = {2014}, date = {2014-01-01}, journal = {Database : the journal of biological databases and curation}, volume = {2014}, pages = {1--10}, abstract = {In 2012 an estimated 8.6 million people developed tuberculosis (TB) and 1.3 million died from the disease [including 320 000 deaths among human immunodeficiency virus (HIV)-positive people]. There is an urgent need for new anti-TB drugs owing to the following: the fact that current treatments have severe side effects, the increasing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the negative drug-drug interactions with certain HIV (or other disease) treatments and the ineffectiveness against dormant Mtb. In this context we present here the TuberQ database, a novel resource for all researchers working in the field of drug development in TB. The main feature of TuberQ is to provide a druggability analysis of Mtb proteins in a consistent and effective manner, contributing to a better selection of potential drug targets for screening campaigns and the analysis of targets for structure-based drug design projects. The structural druggability analysis is combined with features related to the characteristics of putative inhibitor binding pockets and with functional and biological data of proteins. The structural analysis is performed on all available unique Mtb structures and high-quality structural homology-based models. This information is shown in an interactive manner, depicting the protein structure, the pockets and the associated characteristics for each protein. TuberQ also provides information about gene essentiality information, as determined from whole cell-based knockout experiments, and expression information obtained from microarray experiments done in different stress-related conditions. We hope that TuberQ will be a powerful tool for researchers working in TB and eventually will lead to the identification of novel putative targets and progresses in therapeutic activities. Database URL: http://tuberq.proteinq.com.ar/}, keywords = {}, pubstate = {published}, tppubtype = {article} } In 2012 an estimated 8.6 million people developed tuberculosis (TB) and 1.3 million died from the disease [including 320 000 deaths among human immunodeficiency virus (HIV)-positive people]. There is an urgent need for new anti-TB drugs owing to the following: the fact that current treatments have severe side effects, the increasing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the negative drug-drug interactions with certain HIV (or other disease) treatments and the ineffectiveness against dormant Mtb. In this context we present here the TuberQ database, a novel resource for all researchers working in the field of drug development in TB. The main feature of TuberQ is to provide a druggability analysis of Mtb proteins in a consistent and effective manner, contributing to a better selection of potential drug targets for screening campaigns and the analysis of targets for structure-based drug design projects. The structural druggability analysis is combined with features related to the characteristics of putative inhibitor binding pockets and with functional and biological data of proteins. The structural analysis is performed on all available unique Mtb structures and high-quality structural homology-based models. This information is shown in an interactive manner, depicting the protein structure, the pockets and the associated characteristics for each protein. TuberQ also provides information about gene essentiality information, as determined from whole cell-based knockout experiments, and expression information obtained from microarray experiments done in different stress-related conditions. We hope that TuberQ will be a powerful tool for researchers working in TB and eventually will lead to the identification of novel putative targets and progresses in therapeutic activities. Database URL: http://tuberq.proteinq.com.ar/ |
Aymami, Juan; Barril, Xavier; Rodriguez-Pascau, Laura; Martinell, Marc Pharmacological chaperones for enzyme enhancement therapy in genetic diseases. Pharmaceutical patent analyst, 2 (1), pp. 109–124, 2013, ISSN: 2046-8962 (Electronic). @article{Aymami2013, title = {Pharmacological chaperones for enzyme enhancement therapy in genetic diseases.}, author = { Juan Aymami and Xavier Barril and Laura Rodriguez-Pascau and Marc Martinell}, url = {http://dx.doi.org/10.4155/ppa.12.74}, issn = {2046-8962 (Electronic)}, year = {2013}, date = {2013-01-01}, journal = {Pharmaceutical patent analyst}, volume = {2}, number = {1}, pages = {109--124}, abstract = {Pharmacological chaperone therapy (PCT) is a rather new approach consisting in targeting incorrectly folded proteins by small molecules, thus, facilitating the correct folding of the protein and inducing a recovery of its functionality. Many diseases result from mutations on specific genes; this patent review focuses on those pathologies where PCT has a potential application for enzymatic enhancement. Rare diseases are the main area where PCT has been applied and the most advanced compounds are aiming to cure lysosomal storage disorders such as Fabry, Pompe or Gaucher. Until now, most compounds used as pharmacological chaperones were based on substrate-like chemical structures but recently new nonsubstrate-like and non-inhibitory compounds have been disclosed for Gaucher and Pompe diseases. This initiates a new era for pharmacological chaperones with more diverse chemical structures and binding modes. This review covers the patents relating to enzyme enhancement on pharmacological chaperone therapy. Only an update is presented for Gaucher disease, where PCT is highly applied and recently reviewed.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Pharmacological chaperone therapy (PCT) is a rather new approach consisting in targeting incorrectly folded proteins by small molecules, thus, facilitating the correct folding of the protein and inducing a recovery of its functionality. Many diseases result from mutations on specific genes; this patent review focuses on those pathologies where PCT has a potential application for enzymatic enhancement. Rare diseases are the main area where PCT has been applied and the most advanced compounds are aiming to cure lysosomal storage disorders such as Fabry, Pompe or Gaucher. Until now, most compounds used as pharmacological chaperones were based on substrate-like chemical structures but recently new nonsubstrate-like and non-inhibitory compounds have been disclosed for Gaucher and Pompe diseases. This initiates a new era for pharmacological chaperones with more diverse chemical structures and binding modes. This review covers the patents relating to enzyme enhancement on pharmacological chaperone therapy. Only an update is presented for Gaucher disease, where PCT is highly applied and recently reviewed. |
Forti, Flavio; Cavasotto, Claudio; Orozco, Modesto; Barril, Xavier; Luque, Javier A Multilevel Strategy for the Exploration of the Conformational Flexibility of Small Molecules. Journal of chemical theory and computation, 8 (5), pp. 1808–1819, 2012, ISSN: 1549-9618 (Print). @article{Forti2012, title = {A Multilevel Strategy for the Exploration of the Conformational Flexibility of Small Molecules.}, author = { Flavio Forti and Claudio N Cavasotto and Modesto Orozco and Xavier Barril and F Javier Luque}, url = {http://dx.doi.org/10.1021/ct300097s}, issn = {1549-9618 (Print)}, year = {2012}, date = {2012-05-01}, journal = {Journal of chemical theory and computation}, volume = {8}, number = {5}, pages = {1808--1819}, abstract = {Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol. |
Seco, Jesus; Ferrer-Costa, Carles; Campanera, Josep; Soliva, Robert; Barril, Xavier Proteins, 80 (1), pp. 269–80, 2012, ISSN: 1097-0134. @article{Seco2012, title = {Allosteric regulation of PKCθ: understanding multistep phosphorylation and priming by ligands in AGC kinases.}, author = { Jesus Seco and Carles Ferrer-Costa and Josep M Campanera and Robert Soliva and Xavier Barril}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22072623}, issn = {1097-0134}, year = {2012}, date = {2012-01-01}, journal = {Proteins}, volume = {80}, number = {1}, pages = {269--80}, abstract = {Protein kinases play critical roles in cellular activation and differentiation, and are involved in numerous pathophysiological processes. As a critical component of the regulatory circuitry of the cell, the kinase domain has the ability to integrate multiple signals, yielding a predetermined output. In PKC and other protein kinases of the AGC family, several phosphorylation sites control the activity, but these are in turn influenced by the presence of ligands in the binding pocket, which promotes phosphorylation. Here, we take PKC-theta as a prototypical member of the family and use molecular dynamics simulations to investigate the cross-talk that exists between regulatory and functional sites. We first show how the apo-unphosphorylated form of the kinase is populating a conformational space in which access to the ATP binding site and to the activation loop (AL) are simultaneously hindered. This could explain why the inactive state is not only catalytically incompetent but also resistant to activation. AL phosphorylation induces ATP binding site opening, which can then readily accept the cofactor. But the signal transmission mechanism works both ways, and if ligand binding to the unphosphorylated form occurs first, the AL is de-protected and becomes exposed to phosphorylation, thus providing an explanation for the paradoxical activation of PKCs by their inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Protein kinases play critical roles in cellular activation and differentiation, and are involved in numerous pathophysiological processes. As a critical component of the regulatory circuitry of the cell, the kinase domain has the ability to integrate multiple signals, yielding a predetermined output. In PKC and other protein kinases of the AGC family, several phosphorylation sites control the activity, but these are in turn influenced by the presence of ligands in the binding pocket, which promotes phosphorylation. Here, we take PKC-theta as a prototypical member of the family and use molecular dynamics simulations to investigate the cross-talk that exists between regulatory and functional sites. We first show how the apo-unphosphorylated form of the kinase is populating a conformational space in which access to the ATP binding site and to the activation loop (AL) are simultaneously hindered. This could explain why the inactive state is not only catalytically incompetent but also resistant to activation. AL phosphorylation induces ATP binding site opening, which can then readily accept the cofactor. But the signal transmission mechanism works both ways, and if ligand binding to the unphosphorylated form occurs first, the AL is de-protected and becomes exposed to phosphorylation, thus providing an explanation for the paradoxical activation of PKCs by their inhibitors. |
Barril, Xavier; Luque, Javier Molecular simulation methods in drug discovery: A prospective outlook Journal of Computer-Aided Molecular Design, 26 , pp. 81–86, 2012, ISSN: 0920654X. @article{Barril2012, title = {Molecular simulation methods in drug discovery: A prospective outlook}, author = { Xavier Barril and F. Javier Luque}, url = {http://dx.doi.org/10.1007/s10822-011-9506-1}, issn = {0920654X}, year = {2012}, date = {2012-01-01}, journal = {Journal of Computer-Aided Molecular Design}, volume = {26}, pages = {81--86}, abstract = {Over the last decades, molecular simulations have spread through the drug discovery arena. This trend is expected to continue in the foreseeable future thanks to increased performance and the positive impact they can exert on productivity. In this article we highlight three aspects of molecular modelling for which we expect significant improvements over the next 25 years. Increased computational resources, faster algorithms and novel methods to sample rare events will provide a better handle on target flexibility and its relation with ligand binding. More accurate target druggability predictions will improve the success, but also broaden the scope of target-based drug discovery strategies. Finally, the use of higher levels of theory will increase the accuracy of protein-ligand binding affinity predictions, resulting in better hit identification success rates as well as more efficient lead optimization processes.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Over the last decades, molecular simulations have spread through the drug discovery arena. This trend is expected to continue in the foreseeable future thanks to increased performance and the positive impact they can exert on productivity. In this article we highlight three aspects of molecular modelling for which we expect significant improvements over the next 25 years. Increased computational resources, faster algorithms and novel methods to sample rare events will provide a better handle on target flexibility and its relation with ligand binding. More accurate target druggability predictions will improve the success, but also broaden the scope of target-based drug discovery strategies. Finally, the use of higher levels of theory will increase the accuracy of protein-ligand binding affinity predictions, resulting in better hit identification success rates as well as more efficient lead optimization processes. |
Schmidtke, Peter; Bidon-Chanal, Axel; Luque, Javier; Barril, Xavier MDpocket: open-source cavity detection and characterization on molecular dynamics trajectories. Bioinformatics (Oxford, England), 27 (23), pp. 3276–85, 2011, ISSN: 1367-4811. @article{Schmidtke2011, title = {MDpocket: open-source cavity detection and characterization on molecular dynamics trajectories.}, author = { Peter Schmidtke and Axel Bidon-Chanal and F Javier Luque and Xavier Barril}, url = {http://bioinformatics.oxfordjournals.org/content/27/23/3276.abstract}, issn = {1367-4811}, year = {2011}, date = {2011-12-01}, journal = {Bioinformatics (Oxford, England)}, volume = {27}, number = {23}, pages = {3276--85}, abstract = {A variety of pocket detection algorithms are now freely or commercially available to the scientific community for the analysis of static protein structures. However, since proteins are dynamic entities, enhancing the capabilities of these programs for the straightforward detection and characterization of cavities taking into account protein conformational ensembles should be valuable for capturing the plasticity of pockets, and therefore allow gaining insight into structure-function relationships.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A variety of pocket detection algorithms are now freely or commercially available to the scientific community for the analysis of static protein structures. However, since proteins are dynamic entities, enhancing the capabilities of these programs for the straightforward detection and characterization of cavities taking into account protein conformational ensembles should be valuable for capturing the plasticity of pockets, and therefore allow gaining insight into structure-function relationships. |
Schmidtke, Peter; Luque, Javier; Murray, James; Barril, Xavier Shielded hydrogen bonds as structural determinants of binding kinetics: application in drug design. Journal of the American Chemical Society, 133 (46), pp. 18903–10, 2011, ISSN: 1520-5126. @article{Schmidtke2011a, title = {Shielded hydrogen bonds as structural determinants of binding kinetics: application in drug design.}, author = { Peter Schmidtke and F Javier Luque and James B Murray and Xavier Barril}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21981450 http://pubs.acs.org/doi/abs/10.1021/ja207494u}, issn = {1520-5126}, year = {2011}, date = {2011-11-01}, journal = {Journal of the American Chemical Society}, volume = {133}, number = {46}, pages = {18903--10}, abstract = {Time scale control of molecular interactions is an essential part of biochemical systems, but very little is known about the structural factors governing the kinetics of molecular recognition. In drug design, the lifetime of drug-target complexes is a major determinant of pharmacological effects but the absence of structure-kinetic relationships precludes rational optimization of this property. Here we show that almost buried polar atoms-a common feature on protein binding sites-tend to form hydrogen bonds that are shielded from water. Formation and rupture of this type of hydrogen bonds involves an energetically penalized transition state because it occurs asynchronously with dehydration/rehydration. In consequence, water-shielded hydrogen bonds are exchanged at slower rates. Occurrence of this phenomenon can be anticipated from simple structural analysis, affording a novel tool to interpret and predict structure-kinetics relationships. The validity of this principle has been investigated on two pairs of Hsp90 inhibitors for which detailed thermodynamic and kinetic data has been experimentally determined. The agreement between macroscopic observables and molecular simulations confirms the role of water-shielded hydrogen bonds as kinetic traps and illustrates how our finding could be used as an aid in structure-based drug discovery.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Time scale control of molecular interactions is an essential part of biochemical systems, but very little is known about the structural factors governing the kinetics of molecular recognition. In drug design, the lifetime of drug-target complexes is a major determinant of pharmacological effects but the absence of structure-kinetic relationships precludes rational optimization of this property. Here we show that almost buried polar atoms-a common feature on protein binding sites-tend to form hydrogen bonds that are shielded from water. Formation and rupture of this type of hydrogen bonds involves an energetically penalized transition state because it occurs asynchronously with dehydration/rehydration. In consequence, water-shielded hydrogen bonds are exchanged at slower rates. Occurrence of this phenomenon can be anticipated from simple structural analysis, affording a novel tool to interpret and predict structure-kinetics relationships. The validity of this principle has been investigated on two pairs of Hsp90 inhibitors for which detailed thermodynamic and kinetic data has been experimentally determined. The agreement between macroscopic observables and molecular simulations confirms the role of water-shielded hydrogen bonds as kinetic traps and illustrates how our finding could be used as an aid in structure-based drug discovery. |
Spyrakis, Francesca; BidonChanal, Axel; Barril, Xavier; Luque, Javier Protein flexibility and ligand recognition: challenges for molecular modeling. Current topics in medicinal chemistry, 11 (2), pp. 192–210, 2011, ISSN: 1873-4294 (Electronic). @article{Spyrakis2011, title = {Protein flexibility and ligand recognition: challenges for molecular modeling.}, author = { Francesca Spyrakis and Axel BidonChanal and Xavier Barril and F Javier Luque}, url = {http://www.eurekaselect.com/87135/article}, issn = {1873-4294 (Electronic)}, year = {2011}, date = {2011-01-01}, journal = {Current topics in medicinal chemistry}, volume = {11}, number = {2}, pages = {192--210}, abstract = {The intrinsic dynamics of macromolecules is an essential property to relate the structure of biomolecular systems with their function in the cell. In the field of ligand-receptor recognition, numerous evidences have revealed the limitations of the lock-and-key theory, and the need to elaborate models that take into account the inherent plasticity of biomolecules, such as the induced-fit model or the existence of an ensemble of pre-equilibrated conformations. Depending on the nature of the target system, ligand binding can be associated with small local adjustments in side chains or even the backbone to large-scale motions of structural fragments, domains or even subunits. Reproducing the inherent flexibility of biomolecules has thus become one of the most challenging issues in molecular modeling and simulation studies, as it has direct implications in our understanding of the structure-function relationships, but even in areas such as virtual screening and structure-based drug discovery. Given the intrinsic limitation of conventional simulation tools, only events occurring in short time scales can be reproduced at a high accuracy level through all-atom techniques such as Molecular Dynamics simulations. However, larger structural rearrangements demand the use of enhanced sampling methods relying on modified descriptions of the biomolecular system or the potential surface. This review illustrates the crucial role that structural plasticity plays in mediating ligand recognition through representative examples. In addition, it discusses some of the most powerful computational tools developed to characterize the conformational flexibility in ligand-receptor complexes.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The intrinsic dynamics of macromolecules is an essential property to relate the structure of biomolecular systems with their function in the cell. In the field of ligand-receptor recognition, numerous evidences have revealed the limitations of the lock-and-key theory, and the need to elaborate models that take into account the inherent plasticity of biomolecules, such as the induced-fit model or the existence of an ensemble of pre-equilibrated conformations. Depending on the nature of the target system, ligand binding can be associated with small local adjustments in side chains or even the backbone to large-scale motions of structural fragments, domains or even subunits. Reproducing the inherent flexibility of biomolecules has thus become one of the most challenging issues in molecular modeling and simulation studies, as it has direct implications in our understanding of the structure-function relationships, but even in areas such as virtual screening and structure-based drug discovery. Given the intrinsic limitation of conventional simulation tools, only events occurring in short time scales can be reproduced at a high accuracy level through all-atom techniques such as Molecular Dynamics simulations. However, larger structural rearrangements demand the use of enhanced sampling methods relying on modified descriptions of the biomolecular system or the potential surface. This review illustrates the crucial role that structural plasticity plays in mediating ligand recognition through representative examples. In addition, it discusses some of the most powerful computational tools developed to characterize the conformational flexibility in ligand-receptor complexes. |
Schmidtke, Peter; Barril, Xavier Journal of medicinal chemistry, 53 (15), pp. 5858–67, 2010, ISSN: 1520-4804. @article{Schmidtke2010, title = {Understanding and predicting druggability. A high-throughput method for detection of drug binding sites.}, author = { Peter Schmidtke and Xavier Barril}, url = {https://doi.org/10.1021/jm100574m}, doi = {10.1021/jm100574m}, issn = {1520-4804}, year = {2010}, date = {2010-08-01}, journal = {Journal of medicinal chemistry}, volume = {53}, number = {15}, pages = {5858--67}, abstract = {Druggability predictions are important to avoid intractable targets and to focus drug discovery efforts on sites offering better prospects. However, few druggability prediction tools have been released and none has been extensively tested. Here, a set of druggable and nondruggable cavities has been compiled in a collaborative platform ( http://fpocket.sourceforge.net/dcd ) that can be used, contributed, and curated by the community. Druggable binding sites are often oversimplified as closed, hydrophobic cavities, but data set analysis reveals that polar groups in druggable binding sites have properties that enable them to play a decisive role in ligand recognition. Finally, the data set has been used in conjunction with the open source fpocket suite to train and validate a logistic model. State of the art performance was achieved for predicting druggability on known binding sites and on virtual screening experiments where druggable pockets are retrieved from a pool of decoys. The algorithm is free, extremely fast, and can effectively be used to automatically sieve through massive collections of structures ( http://fpocket.sourceforge.net ).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Druggability predictions are important to avoid intractable targets and to focus drug discovery efforts on sites offering better prospects. However, few druggability prediction tools have been released and none has been extensively tested. Here, a set of druggable and nondruggable cavities has been compiled in a collaborative platform ( http://fpocket.sourceforge.net/dcd ) that can be used, contributed, and curated by the community. Druggable binding sites are often oversimplified as closed, hydrophobic cavities, but data set analysis reveals that polar groups in druggable binding sites have properties that enable them to play a decisive role in ligand recognition. Finally, the data set has been used in conjunction with the open source fpocket suite to train and validate a logistic model. State of the art performance was achieved for predicting druggability on known binding sites and on virtual screening experiments where druggable pockets are retrieved from a pool of decoys. The algorithm is free, extremely fast, and can effectively be used to automatically sieve through massive collections of structures ( http://fpocket.sourceforge.net ). |
Novoa, Eva Maria; Pouplana, Lluis Ribas De; Barril, Xavier; Orozco, Modesto Ensemble Docking from Homology Models Journal of Chemical Theory and Computation, 6 , pp. 2547–2557, 2010. @article{Novoa2010, title = {Ensemble Docking from Homology Models}, author = { Eva Maria Novoa and Lluis Ribas De Pouplana and Xavier Barril and Modesto Orozco}, url = {http://pubs.acs.org/doi/abs/10.1021/ct100246y}, year = {2010}, date = {2010-01-01}, journal = {Journal of Chemical Theory and Computation}, volume = {6}, pages = {2547--2557}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Seco, Jesus; Luque, Javier; Barril, Xavier Binding site detection and druggability index from first principles. Journal of medicinal chemistry, 52 (8), pp. 2363–71, 2009, ISSN: 1520-4804. @article{Seco2009, title = {Binding site detection and druggability index from first principles.}, author = { Jesus Seco and F Javier Luque and Xavier Barril}, url = {http://pubs.acs.org/doi/abs/10.1021/jm801385d}, issn = {1520-4804}, year = {2009}, date = {2009-04-01}, journal = {Journal of medicinal chemistry}, volume = {52}, number = {8}, pages = {2363--71}, abstract = {In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using molecular dynamics with a binary solvent. Furthermore, analysis of the simulations give direct access to interaction free energies between the protein and small organic molecules, which can be used to detect binding sites and to predict the maximal affinity that a drug-like molecule could attain for them. On a set of pharmacologically relevant proteins, we obtain good predictions for druggable sites as well as for protein-protein and low affinity binding sites. This is the first druggability index not based on surface descriptors and, being independent of a training set, is particularly indicated to study unconventional targets such as protein-protein interactions or allosteric binding sites.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using molecular dynamics with a binary solvent. Furthermore, analysis of the simulations give direct access to interaction free energies between the protein and small organic molecules, which can be used to detect binding sites and to predict the maximal affinity that a drug-like molecule could attain for them. On a set of pharmacologically relevant proteins, we obtain good predictions for druggable sites as well as for protein-protein and low affinity binding sites. This is the first druggability index not based on surface descriptors and, being independent of a training set, is particularly indicated to study unconventional targets such as protein-protein interactions or allosteric binding sites. |
Butler, Keith; Luque, Javier; Barril, Xavier Toward accurate relative energy predictions of the bioactive conformation of drugs. Journal of computational chemistry, 30 (4), pp. 601–610, 2009, ISSN: 1096-987X (Electronic). @article{Butler2009, title = {Toward accurate relative energy predictions of the bioactive conformation of drugs.}, author = { Keith T Butler and F Javier Luque and Xavier Barril}, url = {http://dx.doi.org/10.1002/jcc.21087}, issn = {1096-987X (Electronic)}, year = {2009}, date = {2009-03-01}, journal = {Journal of computational chemistry}, volume = {30}, number = {4}, pages = {601--610}, abstract = {Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol(-1) of a local minimum, with penalties above 2.0 kcal mol(-1) being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol(-1) of a local minimum, with penalties above 2.0 kcal mol(-1) being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery. |
Marco-contelles, Jose; Leo, Rafael; Ri, De Los; Samadi, Abdelouahid; Bartolini, Manuela; Andrisano, Vincenza; Huertas, Oscar; Barril, Xavier; Luque, Javier; Rodri, Mari; Lo, Manuela; Garci, Antonio; Villarroya, Mercedes Journal of Medicinal Chemistry, 52 , pp. 2724–2732, 2009, ISBN: 0022-2623. @article{Marco-contelles2009, title = {Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease.}, author = { Jose Marco-contelles and Rafael Leo and De Los Ri and Abdelouahid Samadi and Manuela Bartolini and Vincenza Andrisano and Oscar Huertas and Xavier Barril and F Javier Luque and Mari I Rodri and Manuela G Lo and Antonio G Garci and Mercedes Villarroya}, url = {http://dx.doi.org/10.1021/jm801292b}, isbn = {0022-2623}, year = {2009}, date = {2009-01-01}, journal = {Journal of Medicinal Chemistry}, volume = {52}, pages = {2724--2732}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Brough, Paul; Barril, Xavier; Borgognoni, Jenifer; Chene, Patrick; Davies, Nicholas; Davis, Ben; Drysdale, Martin; Dymock, Brian; Eccles, Suzanne; Garcia-Echeverria, Carlos; Fromont, Christophe; Hayes, Angela; Hubbard, Roderick; Jordan, Allan; Jensen, Michael Rugaard; Massey, Andrew; Merrett, Angela; Padfield, Antony; Parsons, Rachel; Radimerski, Thomas; Raynaud, Florence; Robertson, Alan; Roughley, Stephen; Schoepfer, Joseph; Simmonite, Heather; Sharp, Swee; Surgenor, Allan; Valenti, Melanie; Walls, Steven; Webb, Paul; Wood, Mike; Workman, Paul; Wright, Lisa Journal of Medicinal Chemistry, 52 (15), pp. 4794–4809, 2009, ISSN: 00222623. @article{Brough2009, title = {Combining hit identification strategies: Fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone}, author = { Paul A. Brough and Xavier Barril and Jenifer Borgognoni and Patrick Chene and Nicholas G M Davies and Ben Davis and Martin J. Drysdale and Brian Dymock and Suzanne A. Eccles and Carlos Garcia-Echeverria and Christophe Fromont and Angela Hayes and Roderick E. Hubbard and Allan M. Jordan and Michael Rugaard Jensen and Andrew Massey and Angela Merrett and Antony Padfield and Rachel Parsons and Thomas Radimerski and Florence I. Raynaud and Alan Robertson and Stephen D. Roughley and Joseph Schoepfer and Heather Simmonite and Swee Y. Sharp and Allan Surgenor and Melanie Valenti and Steven Walls and Paul Webb and Mike Wood and Paul Workman and Lisa Wright}, url = {http://dx.doi.org/10.1021/jm900357y}, issn = {00222623}, year = {2009}, date = {2009-01-01}, journal = {Journal of Medicinal Chemistry}, volume = {52}, number = {15}, pages = {4794--4809}, abstract = {Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model. |
Eccles, Suzanne; Massey, Andy; Raynaud, Florence; Sharp, Swee; Box, Gary; Valenti, Melanie; Patterson, Lisa; de Brandon, Alexis Haven; Gowan, Sharon; Boxall, Frances; Aherne, Wynne; Rowlands, Martin; Hayes, Angela; Martins, Vanessa; Urban, Frederique; Boxall, Kathy; Prodromou, Chrisostomos; Pearl, Laurence; James, Karen; Matthews, Thomas; Cheung, Kwai-Ming; Kalusa, Andrew; Jones, Keith; McDonald, Edward; Barril, Xavier; Brough, Paul; Cansfield, Julie; Dymock, Brian; Drysdale, Martin; Finch, Harry; Howes, Rob; Hubbard, Roderick; Surgenor, Alan; Webb, Paul; Wood, Mike; Wright, Lisa; Workman, Paul Cancer research, 68 (8), pp. 2850–2860, 2008, ISSN: 1538-7445 (Electronic). @article{Eccles2008, title = {NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis.}, author = { Suzanne A Eccles and Andy Massey and Florence I Raynaud and Swee Y Sharp and Gary Box and Melanie Valenti and Lisa Patterson and Alexis de Haven Brandon and Sharon Gowan and Frances Boxall and Wynne Aherne and Martin Rowlands and Angela Hayes and Vanessa Martins and Frederique Urban and Kathy Boxall and Chrisostomos Prodromou and Laurence Pearl and Karen James and Thomas P Matthews and Kwai-Ming Cheung and Andrew Kalusa and Keith Jones and Edward McDonald and Xavier Barril and Paul A Brough and Julie E Cansfield and Brian Dymock and Martin J Drysdale and Harry Finch and Rob Howes and Roderick E Hubbard and Alan Surgenor and Paul Webb and Mike Wood and Lisa Wright and Paul Workman}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-07-5256}, issn = {1538-7445 (Electronic)}, year = {2008}, date = {2008-04-01}, journal = {Cancer research}, volume = {68}, number = {8}, pages = {2850--2860}, abstract = {We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. |
Forti, Flavio; Barril, Xavier; Luque, Javier; Orozco, Modesto Extension of the MST continuum solvation model to the RM1 semiempirical Hamiltonian. Journal of computational chemistry, 29 (4), pp. 578–587, 2008, ISSN: 1096-987X (Electronic). @article{Forti2008, title = {Extension of the MST continuum solvation model to the RM1 semiempirical Hamiltonian.}, author = { Flavio Forti and Xavier Barril and F Javier Luque and Modesto Orozco}, url = {http://dx.doi.org/10.1002/jcc.20814}, issn = {1096-987X (Electronic)}, year = {2008}, date = {2008-03-01}, journal = {Journal of computational chemistry}, volume = {29}, number = {4}, pages = {578--587}, abstract = {The need to simulate large-sized molecules or to deal with large series of compounds is a challenging topic in computational chemistry, which has stimulated the development of accurate semiempirical methods, such as the recently reported Recife Model 1 (RM1; J Comput Chem 2006, 27, 1101). Even though RM1 may prove to be of value simply due to the enhanced quantitative accuracy in gas phase, it is unclear how the new parameters optimized for RM1 affect the suitability of this semiempirical Hamiltonian to study chemical processes in condensed phases. To address this question, we report the parametrization of the MST/RM1 continuum model for neutral solutes in water, octanol, chloroform and carbon tetrachloride, and for ions in water. The results are used to discuss the transferability of the solvation parameters implemented in previous MST/AM1 and MST/PM3 models.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The need to simulate large-sized molecules or to deal with large series of compounds is a challenging topic in computational chemistry, which has stimulated the development of accurate semiempirical methods, such as the recently reported Recife Model 1 (RM1; J Comput Chem 2006, 27, 1101). Even though RM1 may prove to be of value simply due to the enhanced quantitative accuracy in gas phase, it is unclear how the new parameters optimized for RM1 affect the suitability of this semiempirical Hamiltonian to study chemical processes in condensed phases. To address this question, we report the parametrization of the MST/RM1 continuum model for neutral solutes in water, octanol, chloroform and carbon tetrachloride, and for ions in water. The results are used to discuss the transferability of the solvation parameters implemented in previous MST/AM1 and MST/PM3 models. |
Brough, Paul; Aherne, Wynne; Barril, Xavier; Borgognoni, Jenifer; Boxall, Kathy; Cansfield, Julie; Cheung, Kwai-Ming; Collins, Ian; Davies, Nicholas; Drysdale, Martin; Dymock, Brian; Eccles, Suzanne; Finch, Harry; Fink, Alexandra; Hayes, Angela; Howes, Robert; Hubbard, Roderick; James, Karen; Jordan, Allan; Lockie, Andrea; Martins, Vanessa; Massey, Andrew; Matthews, Thomas; McDonald, Edward; Northfield, Christopher; Pearl, Laurence; Prodromou, Chrisostomos; Ray, Stuart; Raynaud, Florence; Roughley, Stephen; Sharp, Swee; Surgenor, Allan; Walmsley, Lee; Webb, Paul; Wood, Mike; Workman, Paul; Wright, Lisa Journal of medicinal chemistry, 51 (2), pp. 196–218, 2008, ISSN: 0022-2623 (Print). @article{Brough2008, title = {4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.}, author = { Paul A Brough and Wynne Aherne and Xavier Barril and Jenifer Borgognoni and Kathy Boxall and Julie E Cansfield and Kwai-Ming J Cheung and Ian Collins and Nicholas G M Davies and Martin J Drysdale and Brian Dymock and Suzanne A Eccles and Harry Finch and Alexandra Fink and Angela Hayes and Robert Howes and Roderick E Hubbard and Karen James and Allan M Jordan and Andrea Lockie and Vanessa Martins and Andrew Massey and Thomas P Matthews and Edward McDonald and Christopher J Northfield and Laurence H Pearl and Chrisostomos Prodromou and Stuart Ray and Florence I Raynaud and Stephen D Roughley and Swee Y Sharp and Allan Surgenor and D Lee Walmsley and Paul Webb and Mike Wood and Paul Workman and Lisa Wright}, url = {http://dx.doi.org/10.1021/jm701018h}, issn = {0022-2623 (Print)}, year = {2008}, date = {2008-01-01}, journal = {Journal of medicinal chemistry}, volume = {51}, number = {2}, pages = {196--218}, abstract = {Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%. |
León, Rafael; de los Ríos, Cristóbal; Marco-Contelles, José; Huertas, Oscar; Barril, Xavier; Luque, Javier; López, Manuela; García, Antonio; Villarroya, Mercedes Bioorganic and Medicinal Chemistry, 16 (16), pp. 7759–7769, 2008, ISSN: 09680896. @article{Leon2008, title = {New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties}, author = { Rafael León and Cristóbal de los Ríos and José Marco-Contelles and Oscar Huertas and Xavier Barril and F. Javier Luque and Manuela G. López and Antonio G. García and Mercedes Villarroya}, url = {http://dx.doi.org/10.1016/j.bmc.2008.07.005}, issn = {09680896}, year = {2008}, date = {2008-01-01}, journal = {Bioorganic and Medicinal Chemistry}, volume = {16}, number = {16}, pages = {7759--7769}, abstract = {In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1, 8]naphthyridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca2+] elevation elicited by K+ depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease. © 2008 Elsevier Ltd. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1, 8]naphthyridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca2+] elevation elicited by K+ depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease. © 2008 Elsevier Ltd. All rights reserved. |
Sharp, Swee; Prodromou, Chrisostomos; Boxall, Kathy; Powers, Marissa; Holmes, Joanna; Box, Gary; Matthews, Thomas; Cheung, Kwai-Ming; Kalusa, Andrew; James, Karen; Hayes, Angela; Hardcastle, Anthea; Dymock, Brian; Brough, Paul; Barril, Xavier; Cansfield, Julie; Wright, Lisa; Surgenor, Allan; Foloppe, Nicolas; Hubbard, Roderick; Aherne, Wynne; Pearl, Laurence; Jones, Keith; McDonald, Edward; Raynaud, Florence; Eccles, Sue; Drysdale, Martin; Workman, Paul Molecular cancer therapeutics, 6 (4), pp. 1198–1211, 2007, ISSN: 1535-7163 (Print). @article{Sharp2007, title = {Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.}, author = { Swee Y Sharp and Chrisostomos Prodromou and Kathy Boxall and Marissa V Powers and Joanna L Holmes and Gary Box and Thomas P Matthews and Kwai-Ming J Cheung and Andrew Kalusa and Karen James and Angela Hayes and Anthea Hardcastle and Brian Dymock and Paul A Brough and Xavier Barril and Julie E Cansfield and Lisa Wright and Allan Surgenor and Nicolas Foloppe and Roderick E Hubbard and Wynne Aherne and Laurence Pearl and Keith Jones and Edward McDonald and Florence Raynaud and Sue Eccles and Martin Drysdale and Paul Workman}, url = {http://dx.doi.org/10.1158/1535-7163.MCT-07-0149}, issn = {1535-7163 (Print)}, year = {2007}, date = {2007-04-01}, journal = {Molecular cancer therapeutics}, volume = {6}, number = {4}, pages = {1198--1211}, abstract = {Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors. |
Munoz-Muriedas, Jordi; Barril, Xavier; Lopez, Jose Maria; Orozco, Modesto; Luque, Francisco Javier A hydrophobic similarity analysis of solvation effects on nucleic acid bases. Journal of molecular modeling, 13 (2), pp. 357–365, 2007, ISSN: 0948-5023 (Electronic). @article{Munoz-Muriedas2007, title = {A hydrophobic similarity analysis of solvation effects on nucleic acid bases.}, author = { Jordi Munoz-Muriedas and Xavier Barril and Jose Maria Lopez and Modesto Orozco and Francisco Javier Luque}, url = {http://dx.doi.org/10.1007/s00894-006-0150-y}, issn = {0948-5023 (Electronic)}, year = {2007}, date = {2007-02-01}, journal = {Journal of molecular modeling}, volume = {13}, number = {2}, pages = {357--365}, abstract = {We investigate the changes in the solvation properties of the natural nucleic acid bases due to the formation of the canonical Watson-Crick hydrogen-bonded complexes. To this end, the changes in the free energy of solvation of the bases induced upon hydrogen-bonded dimerization are analyzed by means of the hydrophobic similarity index, which relies on the atomic contributions to the free energy of solvation determined by the partitioning method implemented in the framework of the MST continuum model. Such an index is also used to examine the hydrophobic similarity between the canonical nucleic acid bases and a series of highly apolar analogues, which have been designed as potential candidates to expand the genetic alphabet. The ability of these analogues to be incorporated into modified DNA duplexes can be related to the large reduction in the hydrophilicity of the natural bases upon formation of the canonical hydrogen-bonded dimers. The results illustrate the suitability of the hydrophobic similarity index to rationalize the role played by solvation in molecular recognition.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We investigate the changes in the solvation properties of the natural nucleic acid bases due to the formation of the canonical Watson-Crick hydrogen-bonded complexes. To this end, the changes in the free energy of solvation of the bases induced upon hydrogen-bonded dimerization are analyzed by means of the hydrophobic similarity index, which relies on the atomic contributions to the free energy of solvation determined by the partitioning method implemented in the framework of the MST continuum model. Such an index is also used to examine the hydrophobic similarity between the canonical nucleic acid bases and a series of highly apolar analogues, which have been designed as potential candidates to expand the genetic alphabet. The ability of these analogues to be incorporated into modified DNA duplexes can be related to the large reduction in the hydrophilicity of the natural bases upon formation of the canonical hydrogen-bonded dimers. The results illustrate the suitability of the hydrophobic similarity index to rationalize the role played by solvation in molecular recognition. |
Barril, Xavier; Soliva, Robert Molecular bioSystems, 2 (12), pp. 660–81, 2006, ISSN: 1742-206X. @article{Barril2006, title = {Molecular modelling.}, author = { Xavier Barril and Robert Soliva}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17216047}, issn = {1742-206X}, year = {2006}, date = {2006-12-01}, journal = {Molecular bioSystems}, volume = {2}, number = {12}, pages = {660--81}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Barril, Xavier; Fradera, Xavier Incorporating protein flexibility into docking and structure-based drug design. Expert opinion on drug discovery, 1 (4), pp. 335–349, 2006, ISSN: 1746-0441 (Print). @article{Barril2006b, title = {Incorporating protein flexibility into docking and structure-based drug design.}, author = { Xavier Barril and Xavier Fradera}, url = {http://dx.doi.org/10.1517/17460441.1.4.335}, issn = {1746-0441 (Print)}, year = {2006}, date = {2006-09-01}, journal = {Expert opinion on drug discovery}, volume = {1}, number = {4}, pages = {335--349}, abstract = {The use of structure in drug design has become widespread, mainly thanks to recent advances in crystallography. Nevertheless, biological macromolecules are intrinsically flexible and it is increasingly evident that their function depends critically on both their structure and dynamics. In this review the authors discuss the implications of protein flexibility for drug design and review recent progress in incorporating protein flexibility into docking and structure-based drug design.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The use of structure in drug design has become widespread, mainly thanks to recent advances in crystallography. Nevertheless, biological macromolecules are intrinsically flexible and it is increasingly evident that their function depends critically on both their structure and dynamics. In this review the authors discuss the implications of protein flexibility for drug design and review recent progress in incorporating protein flexibility into docking and structure-based drug design. |
Barril, Xavier; Beswick, Mandy; Collier, Adam; Drysdale, Martin; Dymock, Brian; Fink, Alexandra; Grant, Kate; Howes, Robert; Jordan, Allan; Massey, Andrew; Surgenor, Allan; Wayne, Joanne; Workman, Paul; Wright, Lisa 4-Amino derivatives of the Hsp90 inhibitor CCT018159. Bioorganic & medicinal chemistry letters, 16 (9), pp. 2543–2548, 2006, ISSN: 0960-894X (Print). @article{Barril2006a, title = {4-Amino derivatives of the Hsp90 inhibitor CCT018159.}, author = { Xavier Barril and Mandy C Beswick and Adam Collier and Martin J Drysdale and Brian W Dymock and Alexandra Fink and Kate Grant and Robert Howes and Allan M Jordan and Andrew Massey and Allan Surgenor and Joanne Wayne and Paul Workman and Lisa Wright}, url = {http://dx.doi.org/10.1016/j.bmcl.2006.01.099}, issn = {0960-894X (Print)}, year = {2006}, date = {2006-05-01}, journal = {Bioorganic & medicinal chemistry letters}, volume = {16}, number = {9}, pages = {2543--2548}, abstract = {Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation. |
Howes,; Barril,; Dymock,; Grant,; Northfield,; Robertson,; Surgenor,; Wayne,; Wright,; James,; Matthews,; Cheung,; McDonald,; Workman,; Drysdale, A fluorescence polarization assay for inhibitors of Hsp90. Analytical biochemistry, 350 (2), pp. 202–213, 2006, ISSN: 0003-2697 (Print). @article{Howes2006, title = {A fluorescence polarization assay for inhibitors of Hsp90.}, author = {R Howes and X Barril and B W Dymock and K Grant and C J Northfield and A G S Robertson and A Surgenor and J Wayne and L Wright and K James and T Matthews and K-M Cheung and E McDonald and P Workman and M J Drysdale}, url = {http://dx.doi.org/10.1016/j.ab.2005.12.023}, issn = {0003-2697 (Print)}, year = {2006}, date = {2006-03-01}, journal = {Analytical biochemistry}, volume = {350}, number = {2}, pages = {202--213}, abstract = {Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a fluorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect affinity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a fluorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect affinity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors. |
Barril, Xavier; Brough, Paul; Drysdale, Martin; Hubbard, Roderick; Massey, Andrew; Surgenor, Allan; Wright, Lisa Structure-based discovery of a new class of Hsp90 inhibitors. Bioorganic & medicinal chemistry letters, 15 (23), pp. 5187–91, 2005, ISSN: 0960-894X. @article{Barril2005, title = {Structure-based discovery of a new class of Hsp90 inhibitors.}, author = { Xavier Barril and Paul Brough and Martin Drysdale and Roderick E Hubbard and Andrew Massey and Allan Surgenor and Lisa Wright}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16202589}, issn = {0960-894X}, year = {2005}, date = {2005-12-01}, journal = {Bioorganic & medicinal chemistry letters}, volume = {15}, number = {23}, pages = {5187--91}, abstract = {Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding site of Hsp90, providing a rationale for the observed activity of the series and suggesting strategies for developing compounds with improved properties. |
Brough, Paul; Barril, Xavier; Beswick, Mandy; Dymock, Brian; Drysdale, Martin; Wright, Lisa; Grant, Kate; Massey, Andrew; Surgenor, Allan; Workman, Paul Bioorganic & medicinal chemistry letters, 15 (23), pp. 5197–5201, 2005, ISSN: 0960-894X (Print). @article{Brough2005, title = {3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone.}, author = { Paul A Brough and Xavier Barril and Mandy Beswick and Brian W Dymock and Martin J Drysdale and Lisa Wright and Kate Grant and Andrew Massey and Allan Surgenor and Paul Workman}, url = {http://dx.doi.org/10.1016/j.bmcl.2005.08.091}, issn = {0960-894X (Print)}, year = {2005}, date = {2005-12-01}, journal = {Bioorganic & medicinal chemistry letters}, volume = {15}, number = {23}, pages = {5197--5201}, abstract = {Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction. |
Dymock, Brian; Barril, Xavier; Brough, Paul; Cansfield, Julie; Massey, Andrew; McDonald, Edward; Hubbard, Roderick; Surgenor, Allan; Roughley, Stephen; Webb, Paul; Workman, Paul; Wright, Lisa; Drysdale, Martin Journal of medicinal chemistry, 48 (13), pp. 4212–4215, 2005, ISSN: 0022-2623 (Print). @article{Dymock2005, title = {Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.}, author = { Brian W Dymock and Xavier Barril and Paul A Brough and Julie E Cansfield and Andrew Massey and Edward McDonald and Roderick E Hubbard and Allan Surgenor and Stephen D Roughley and Paul Webb and Paul Workman and Lisa Wright and Martin J Drysdale}, url = {http://dx.doi.org/10.1021/jm050355z}, issn = {0022-2623 (Print)}, year = {2005}, date = {2005-06-01}, journal = {Journal of medicinal chemistry}, volume = {48}, number = {13}, pages = {4212--4215}, abstract = {The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG. |
Barril, Xavier; Morley, David Journal of medicinal chemistry, 48 (13), pp. 4432–43, 2005, ISSN: 0022-2623. @article{Barril2005a, title = {Unveiling the full potential of flexible receptor docking using multiple crystallographic structures.}, author = { Xavier Barril and S David Morley}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15974595}, issn = {0022-2623}, year = {2005}, date = {2005-06-01}, journal = {Journal of medicinal chemistry}, volume = {48}, number = {13}, pages = {4432--43}, abstract = {One of the current challenges in docking studies is the inclusion of receptor flexibility. This is crucial because the binding sites of many therapeutic targets sample a wide range of conformational states, which has major consequences on molecular recognition. In this paper, we make use of very large sets of X-ray structures of cyclin dependent kinase 2 (CDK2) and heat shock protein 90 (HSP90) to assess the performance of flexible receptor docking in binding-mode prediction and virtual screening experiments. Flexible receptor docking performs much better than rigid receptor docking in the former application. Regarding the latter, we observe a significant improvement in the prediction of binding affinities, but owing to an increase in the number of false positives, this is not translated into better hit rates. A simple scoring scheme to correct this limitation is presented. More importantly, pitfalls inherent to flexible receptor docking have been identified and guidelines are presented to avoid them.}, keywords = {}, pubstate = {published}, tppubtype = {article} } One of the current challenges in docking studies is the inclusion of receptor flexibility. This is crucial because the binding sites of many therapeutic targets sample a wide range of conformational states, which has major consequences on molecular recognition. In this paper, we make use of very large sets of X-ray structures of cyclin dependent kinase 2 (CDK2) and heat shock protein 90 (HSP90) to assess the performance of flexible receptor docking in binding-mode prediction and virtual screening experiments. Flexible receptor docking performs much better than rigid receptor docking in the former application. Regarding the latter, we observe a significant improvement in the prediction of binding affinities, but owing to an increase in the number of false positives, this is not translated into better hit rates. A simple scoring scheme to correct this limitation is presented. More importantly, pitfalls inherent to flexible receptor docking have been identified and guidelines are presented to avoid them. |
Wright, Lisa; Barril, Xavier; Dymock, Brian; Sheridan, Louisa; Surgenor, Allan; Beswick, Mandy; Drysdale, Martin; Collier, Adam; Massey, Andy; Davies, Nick; Fink, Alex; Fromont, Christophe; Aherne, Wynne; Boxall, Kathy; Sharp, Swee; Workman, Paul; Hubbard, Roderick Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms. Chemistry & biology, 11 (6), pp. 775–785, 2004, ISSN: 1074-5521 (Print). @article{Wright2004, title = {Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms.}, author = { Lisa Wright and Xavier Barril and Brian Dymock and Louisa Sheridan and Allan Surgenor and Mandy Beswick and Martin Drysdale and Adam Collier and Andy Massey and Nick Davies and Alex Fink and Christophe Fromont and Wynne Aherne and Kathy Boxall and Swee Sharp and Paul Workman and Roderick E Hubbard}, url = {http://dx.doi.org/10.1016/j.chembiol.2004.03.033}, issn = {1074-5521 (Print)}, year = {2004}, date = {2004-06-01}, journal = {Chemistry & biology}, volume = {11}, number = {6}, pages = {775--785}, abstract = {Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90beta, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90beta, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties. |
Dymock, Brian; Barril, Xavier; Beswick, Mandy; Collier, Adam; Davies, Nicholas; Drysdale, Martin; Fink, Alexandra; Fromont, Christophe; Hubbard, Roderick; Massey, Andrew; Surgenor, Allan; Wright, Lisa Bioorganic & medicinal chemistry letters, 14 (2), pp. 325–328, 2004, ISSN: 0960-894X (Print). @article{Dymock2004, title = {Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures.}, author = { Brian Dymock and Xavier Barril and Mandy Beswick and Adam Collier and Nicholas Davies and Martin Drysdale and Alexandra Fink and Christophe Fromont and Roderick E Hubbard and Andrew Massey and Allan Surgenor and Lisa Wright}, url = {http://www.sciencedirect.com/science/article/pii/S0960894X03011922}, issn = {0960-894X (Print)}, year = {2004}, date = {2004-01-01}, journal = {Bioorganic & medicinal chemistry letters}, volume = {14}, number = {2}, pages = {325--328}, abstract = {Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors. |
Baurin, Nicolas; Aboul-Ela, Fareed; Barril, Xavier; Davis, Ben; Drysdale, Martin; Dymock, Brian; Finch, Harry; Fromont, Christophe; Richardson, Christine; Simmonite, Heather; Hubbard, Roderick Journal of chemical information and computer sciences, 44 (6), pp. 2157–66, 2004, ISSN: 0095-2338. @article{Baurin2004, title = {Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets.}, author = { Nicolas Baurin and Fareed Aboul-Ela and Xavier Barril and Ben Davis and Martin Drysdale and Brian Dymock and Harry Finch and Christophe Fromont and Christine Richardson and Heather Simmonite and Roderick E Hubbard}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15554686}, issn = {0095-2338}, year = {2004}, date = {2004-01-01}, journal = {Journal of chemical information and computer sciences}, volume = {44}, number = {6}, pages = {2157--66}, abstract = {We have designed four generations of a low molecular weight fragment library for use in NMR-based screening against protein targets. The library initially contained 723 fragments which were selected manually from the Available Chemicals Directory. A series of in silico filters and property calculations were developed to automate the selection process, allowing a larger database of 1.79 M available compounds to be searched for a further 357 compounds that were added to the library. A kinase binding pharmacophore was then derived to select 174 kinase-focused fragments. Finally, an additional 61 fragments were selected to increase the number of different pharmacophores represented within the library. All of the fragments added to the library passed quality checks to ensure they were suitable for the screening protocol, with appropriate solubility, purity, chemical stability, and unambiguous NMR spectrum. The successive generations of libraries have been characterized through analysis of structural properties (molecular weight, lipophilicity, polar surface area, number of rotatable bonds, and hydrogen-bonding potential) and by analyzing their pharmacophoric complexity. These calculations have been used to compare the fragment libraries with a drug-like reference set of compounds and a set of molecules that bind to protein active sites. In addition, an analysis of the overall results of screening the library against the ATP binding site of two protein targets (HSP90 and CDK2) reveals different patterns of fragment binding, demonstrating that the approach can find selective compounds that discriminate between related binding sites.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We have designed four generations of a low molecular weight fragment library for use in NMR-based screening against protein targets. The library initially contained 723 fragments which were selected manually from the Available Chemicals Directory. A series of in silico filters and property calculations were developed to automate the selection process, allowing a larger database of 1.79 M available compounds to be searched for a further 357 compounds that were added to the library. A kinase binding pharmacophore was then derived to select 174 kinase-focused fragments. Finally, an additional 61 fragments were selected to increase the number of different pharmacophores represented within the library. All of the fragments added to the library passed quality checks to ensure they were suitable for the screening protocol, with appropriate solubility, purity, chemical stability, and unambiguous NMR spectrum. The successive generations of libraries have been characterized through analysis of structural properties (molecular weight, lipophilicity, polar surface area, number of rotatable bonds, and hydrogen-bonding potential) and by analyzing their pharmacophoric complexity. These calculations have been used to compare the fragment libraries with a drug-like reference set of compounds and a set of molecules that bind to protein active sites. In addition, an analysis of the overall results of screening the library against the ATP binding site of two protein targets (HSP90 and CDK2) reveals different patterns of fragment binding, demonstrating that the approach can find selective compounds that discriminate between related binding sites. |
Barril, Xavier; Hubbard,; Morley, Virtual Screening in Structure-Based Drug Discovery Mini Reviews in Medicinal Chemistry, 4 (7), pp. 779–791, 2004. @article{barril2004, title = {Virtual Screening in Structure-Based Drug Discovery}, author = { Xavier Barril and R E Hubbard and S D Morley}, url = {http://www.ingentaconnect.com/content/ben/mrmc/2004/00000004/00000007/art00009}, year = {2004}, date = {2004-01-01}, journal = {Mini Reviews in Medicinal Chemistry}, volume = {4}, number = {7}, pages = {779--791}, abstract = {Recent advances in structure determination and computational methods have encouraged the development of structure-based virtual screening. Here we survey progress in the field and review the most recent methods, validation experiments and real applications, including an in-house example of hit identification for the oncology target Hsp90. These results provide a basis for discussing the current state of structure-based virtual screening and to outline the developments that are expected to have a major impact in the near future.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Recent advances in structure determination and computational methods have encouraged the development of structure-based virtual screening. Here we survey progress in the field and review the most recent methods, validation experiments and real applications, including an in-house example of hit identification for the oncology target Hsp90. These results provide a basis for discussing the current state of structure-based virtual screening and to outline the developments that are expected to have a major impact in the near future. |
Curutchet,; Salichs,; Barril,; Orozco, Modesto; Luque, Javier Journal of computational chemistry, 24 (1), pp. 32–45, 2003, ISSN: 0192-8651 (Print). @article{Curutchet2003a, title = {Transferability of fragmental contributions to the octanol/water partition coefficient: an NDDO-based MST study.}, author = { C Curutchet and A Salichs and X Barril and Modesto Orozco and F Javier Luque}, url = {http://dx.doi.org/10.1002/jcc.10155}, issn = {0192-8651 (Print)}, year = {2003}, date = {2003-01-01}, journal = {Journal of computational chemistry}, volume = {24}, number = {1}, pages = {32--45}, abstract = {This study examines the transferability of fragmental contributions to the octanol/water partition coefficient. As a previous step, we report the parameterization of the AM1 and PM3 versions of the MST model for n-octanol. The final AM1 and PM3 MST models reproduce the experimental free energy of solvation and the octanol/water partition coefficient (log P(ow)) with a root-mean-square deviation of around 0.7 kcal/mol and 0.5 (in units of log P), respectively. Based on this parameterization, an NNDO-based procedure is presented to dissect the free energy of transfer between octanol and water in contributions directly associated with specific atoms or functional groups. The application of this procedure to a set of representative molecular systems illustrates the dependence of the log P(ow) fragmental contribution due to electronic, hydrogen bonding, and steric effects, which cannot be easily accounted for in simple additive-based empirical schemes. The results point out the potential use of theoretical methods to refine the fragmental contributions in empirical methods.}, keywords = {}, pubstate = {published}, tppubtype = {article} } This study examines the transferability of fragmental contributions to the octanol/water partition coefficient. As a previous step, we report the parameterization of the AM1 and PM3 versions of the MST model for n-octanol. The final AM1 and PM3 MST models reproduce the experimental free energy of solvation and the octanol/water partition coefficient (log P(ow)) with a root-mean-square deviation of around 0.7 kcal/mol and 0.5 (in units of log P), respectively. Based on this parameterization, an NNDO-based procedure is presented to dissect the free energy of transfer between octanol and water in contributions directly associated with specific atoms or functional groups. The application of this procedure to a set of representative molecular systems illustrates the dependence of the log P(ow) fragmental contribution due to electronic, hydrogen bonding, and steric effects, which cannot be easily accounted for in simple additive-based empirical schemes. The results point out the potential use of theoretical methods to refine the fragmental contributions in empirical methods. |
Munoz,; Barril,; Hernandez,; Orozco, Modesto; Luque, Javier Hydrophobic similarity between molecules: a MST-based hydrophobic similarity index. Journal of computational chemistry, 23 (5), pp. 554–563, 2002, ISSN: 0192-8651 (Print). @article{Munoz2002, title = {Hydrophobic similarity between molecules: a MST-based hydrophobic similarity index.}, author = { J Munoz and X Barril and B Hernandez and Modesto Orozco and F Javier Luque}, url = {http://dx.doi.org/10.1002/jcc.10055}, issn = {0192-8651 (Print)}, year = {2002}, date = {2002-04-01}, journal = {Journal of computational chemistry}, volume = {23}, number = {5}, pages = {554--563}, abstract = {A similarity index based on the hydrophilic/hydrophobic properties of molecules is presented. Such an index is defined based on the fractional partition of the free energy of solvation developed within the framework of the self-consistent reaction field MST model, which divides the free energy of solvation or the free energy of transfer into contributions assigned to the surface elements defining the solute/solvent interface. These surface contributions can be integrated to derive atomic or group contributions. The suitability of the index to compute the molecular similarity based on hydrophobic/hydrophilic properties is examined by considering their application in a variety of test systems, including structure-activity relationships, absorption properties, and molecular recognition. The similarity index is expected to be a very powerful tool in molecular similarity studies for compounds of chemical, biochemical, and pharmaceutical interest.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A similarity index based on the hydrophilic/hydrophobic properties of molecules is presented. Such an index is defined based on the fractional partition of the free energy of solvation developed within the framework of the self-consistent reaction field MST model, which divides the free energy of solvation or the free energy of transfer into contributions assigned to the surface elements defining the solute/solvent interface. These surface contributions can be integrated to derive atomic or group contributions. The suitability of the index to compute the molecular similarity based on hydrophobic/hydrophilic properties is examined by considering their application in a variety of test systems, including structure-activity relationships, absorption properties, and molecular recognition. The similarity index is expected to be a very powerful tool in molecular similarity studies for compounds of chemical, biochemical, and pharmaceutical interest. |
Dvir,; Wong,; Harel,; Barril,; Orozco,; Luque,; Munoz-Torrero,; Camps,; Rosenberry,; Silman,; Sussman, Biochemistry, 41 (9), pp. 2970–2981, 2002, ISSN: 0006-2960 (Print). @article{Dvir2002, title = {3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 A resolution: kinetic and molecular dynamic correlates.}, author = { H Dvir and D M Wong and M Harel and X Barril and M Orozco and F J Luque and D Munoz-Torrero and P Camps and T L Rosenberry and I Silman and J L Sussman}, url = {http://pubs.acs.org/doi/abs/10.1021/bi011652i}, issn = {0006-2960 (Print)}, year = {2002}, date = {2002-03-01}, journal = {Biochemistry}, volume = {41}, number = {9}, pages = {2970--2981}, abstract = {Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117. |
Barril,; Kalko,; Orozco,; Luque, Rational design of reversible acetylcholinesterase inhibitors. Mini reviews in medicinal chemistry, 2 (1), pp. 27–36, 2002, ISSN: 1389-5575 (Print). @article{Barril2002, title = {Rational design of reversible acetylcholinesterase inhibitors.}, author = { X Barril and S G Kalko and M Orozco and F J Luque}, url = {http://www.eurekaselect.com/81384/article}, issn = {1389-5575 (Print)}, year = {2002}, date = {2002-02-01}, journal = {Mini reviews in medicinal chemistry}, volume = {2}, number = {1}, pages = {27--36}, abstract = {A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors. |
Camps,; Gomez,; Munoz-Torrero,; Badia,; Vivas,; Barril,; Orozco,; Luque, Journal of medicinal chemistry, 44 (26), pp. 4733–4736, 2001, ISSN: 0022-2623 (Print). @article{Camps2001, title = {Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors.}, author = { P Camps and E Gomez and D Munoz-Torrero and A Badia and N M Vivas and X Barril and M Orozco and F J Luque}, url = {http://pubs.acs.org/doi/abs/10.1021/jm010949b}, issn = {0022-2623 (Print)}, year = {2001}, date = {2001-12-01}, journal = {Journal of medicinal chemistry}, volume = {44}, number = {26}, pages = {4733--4736}, abstract = {Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (+/-)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (+/-)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect. |
Gelpi,; Kalko,; Barril,; Cirera,; de Cruz, La; Luque,; Orozco, Proteins, 45 (4), pp. 428–437, 2001, ISSN: 0887-3585 (Print). @article{Gelpi2001, title = {Classical molecular interaction potentials: improved setup procedure in molecular dynamics simulations of proteins.}, author = { J L Gelpi and S G Kalko and X Barril and J Cirera and X de La Cruz and F J Luque and M Orozco}, url = {http://onlinelibrary.wiley.com/doi/10.1002/prot.1159/abstract}, issn = {0887-3585 (Print)}, year = {2001}, date = {2001-12-01}, journal = {Proteins}, volume = {45}, number = {4}, pages = {428--437}, abstract = {The latest version of the classical molecular interaction potential (CMIP) has the ability to predict the position of crystallographic waters in several proteins with great accuracy. This article analyzes the ability of the CMIP functional to improve the setup procedure of the molecular system in molecular dynamics (MD) simulations of proteins. To this end, the CMIP strategy is used to include both water molecules and counterions in different protein systems. The structural details of the configurations sampled from trajectories obtained using the CMIP setup procedure are compared with those obtained from trajectories derived from a standard equilibration process. The results show that standard MD simulations can lead to artifactual results, which are avoided using the CMIP setup procedure. Because the CMIP is easy to implement at a low computational cost, it can be very useful in obtaining reliable MD trajectories.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The latest version of the classical molecular interaction potential (CMIP) has the ability to predict the position of crystallographic waters in several proteins with great accuracy. This article analyzes the ability of the CMIP functional to improve the setup procedure of the molecular system in molecular dynamics (MD) simulations of proteins. To this end, the CMIP strategy is used to include both water molecules and counterions in different protein systems. The structural details of the configurations sampled from trajectories obtained using the CMIP setup procedure are compared with those obtained from trajectories derived from a standard equilibration process. The results show that standard MD simulations can lead to artifactual results, which are avoided using the CMIP setup procedure. Because the CMIP is easy to implement at a low computational cost, it can be very useful in obtaining reliable MD trajectories. |
Barril,; Orozco,; Luque, Towards improved acetylcholinesterase inhibitors: a structural and computational approach. Mini reviews in medicinal chemistry, 1 (3), pp. 255–266, 2001, ISSN: 1389-5575 (Print). @article{Barril2001, title = {Towards improved acetylcholinesterase inhibitors: a structural and computational approach.}, author = { X Barril and M Orozco and F J Luque}, url = {http://www.eurekaselect.com/81562/article}, issn = {1389-5575 (Print)}, year = {2001}, date = {2001-09-01}, journal = {Mini reviews in medicinal chemistry}, volume = {1}, number = {3}, pages = {255--266}, abstract = {During the last years, solving the X-ray crystallographic structure of both the unliganded acetylcholinesterase (AChE) and AChE complexes with various inhibitors has provided valuable knowledge of the interactions that mediate inhibitor binding. This structural information allows us to rationalize differences in binding affinities for related analogues, and more importantly opens new strategies to design compounds with improved pharmacological properties. This is illustrated in the case of the recently reported huprines, which are a new class of very potent and selective acetylcholinesterase inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } During the last years, solving the X-ray crystallographic structure of both the unliganded acetylcholinesterase (AChE) and AChE complexes with various inhibitors has provided valuable knowledge of the interactions that mediate inhibitor binding. This structural information allows us to rationalize differences in binding affinities for related analogues, and more importantly opens new strategies to design compounds with improved pharmacological properties. This is illustrated in the case of the recently reported huprines, which are a new class of very potent and selective acetylcholinesterase inhibitors. |
Camps,; R, El Achab; Morral,; Munoz-Torrero,; Badia,; Banos,; Vivas,; Barril,; Orozco,; Luque, Journal of medicinal chemistry, 43 (24), pp. 4657–4666, 2000, ISSN: 0022-2623 (Print). @article{Camps2000, title = {New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease.}, author = { P Camps and El Achab R and J Morral and D Munoz-Torrero and A Badia and J E Banos and N M Vivas and X Barril and M Orozco and F J Luque}, url = {http://pubs.acs.org/doi/abs/10.1021/jm000980y}, issn = {0022-2623 (Print)}, year = {2000}, date = {2000-11-01}, journal = {Journal of medicinal chemistry}, volume = {43}, number = {24}, pages = {4657--4666}, abstract = {Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds. |
Barril,; Orozco,; Luque, Journal of medicinal chemistry, 42 (25), pp. 5110–5119, 1999, ISSN: 0022-2623 (Print). @article{Barril1999, title = {Predicting relative binding free energies of tacrine-huperzine A hybrids as inhibitors of acetylcholinesterase.}, author = { X Barril and M Orozco and F J Luque}, url = {http://pubs.acs.org/doi/abs/10.1021/jm990371u}, issn = {0022-2623 (Print)}, year = {1999}, date = {1999-12-01}, journal = {Journal of medicinal chemistry}, volume = {42}, number = {25}, pages = {5110--5119}, abstract = {The binding of the 9-methyl derivative of tacrine-huperzine A hybrid to Torpedo californica acetylcholinesterase (AChE) has been studied by computational methods. Molecular dynamics simulations have been performed for the AChE-drug complex considering two different ionization states of the protein and two different orientations of the drug in the binding pocket, which were chosen from a previous screening procedure. Analysis of structural fluctuations and of the pattern of interactions between drug and enzyme clearly favor one binding mode for the tacrine-huperzine A hydrid, which mixes effectively some of the binding features of tacrine and huperzine A. The differences in inhibitory activity for a series of related derivatives have been successfully predicted by free energy calculations, which reinforces the confidence in the binding mode and its usefulness for molecular modeling studies. The same techniques have been used to make de novo predictions for a new 3-fluoro-9-ethyl derivative, which can be used to verify a posteriori the goodness of the binding mode. Finally, we have also investigated the effect of replacing Phe300 in the Torpedo californica enzyme by Tyr, which is present in the human AChE. The results indicate that the Phe330-->Tyr mutation is expected to have little effect on the binding affinities. Overall, the whole of results supports the validity of the putative binding model to explain the binding of tacrine-huperzine A hybrids to AChE.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The binding of the 9-methyl derivative of tacrine-huperzine A hybrid to Torpedo californica acetylcholinesterase (AChE) has been studied by computational methods. Molecular dynamics simulations have been performed for the AChE-drug complex considering two different ionization states of the protein and two different orientations of the drug in the binding pocket, which were chosen from a previous screening procedure. Analysis of structural fluctuations and of the pattern of interactions between drug and enzyme clearly favor one binding mode for the tacrine-huperzine A hydrid, which mixes effectively some of the binding features of tacrine and huperzine A. The differences in inhibitory activity for a series of related derivatives have been successfully predicted by free energy calculations, which reinforces the confidence in the binding mode and its usefulness for molecular modeling studies. The same techniques have been used to make de novo predictions for a new 3-fluoro-9-ethyl derivative, which can be used to verify a posteriori the goodness of the binding mode. Finally, we have also investigated the effect of replacing Phe300 in the Torpedo californica enzyme by Tyr, which is present in the human AChE. The results indicate that the Phe330-->Tyr mutation is expected to have little effect on the binding affinities. Overall, the whole of results supports the validity of the putative binding model to explain the binding of tacrine-huperzine A hybrids to AChE. |
Camps,; Achab, El; Gorbig,; Morral,; Munoz-Torrero,; Badia,; Banos, Eladi; Vivas,; Barril,; Orozco,; Luque, Journal of medicinal chemistry, 42 (17), pp. 3227–3242, 1999, ISSN: 0022-2623 (Print). @article{Camps1999, title = {Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.}, author = { P Camps and R El Achab and D M Gorbig and J Morral and D Munoz-Torrero and A Badia and J Eladi Banos and N M Vivas and X Barril and M Orozco and F J Luque}, url = {http://dx.doi.org/10.1021/jm980620z}, issn = {0022-2623 (Print)}, year = {1999}, date = {1999-08-01}, journal = {Journal of medicinal chemistry}, volume = {42}, number = {17}, pages = {3227--3242}, abstract = {Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A. |
Luque,; Barril,; Orozco, Fractional description of free energies of solvation. Journal of computer-aided molecular design, 13 (2), pp. 139–152, 1999, ISSN: 0920-654X (Print). @article{Luque1999, title = {Fractional description of free energies of solvation.}, author = { F J Luque and X Barril and M Orozco}, url = {http://link.springer.com/article/10.1023/A:1008036526741}, issn = {0920-654X (Print)}, year = {1999}, date = {1999-03-01}, journal = {Journal of computer-aided molecular design}, volume = {13}, number = {2}, pages = {139--152}, abstract = {A new and rigorous method for the fractional description of solvation and transfer free energies is presented. The method is based on the use of the Miertus-Scrocco-Tomasi self-consistent reaction field method (MST-SCRF), and allows for a rigorous partition of the total solvation free energy into surface elements. The method gives a complete picture of the hydrophobicity/hydrophilicity of molecules. Present results allow us to expect that the method might provide useful information in drug design and molecular modeling studies.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A new and rigorous method for the fractional description of solvation and transfer free energies is presented. The method is based on the use of the Miertus-Scrocco-Tomasi self-consistent reaction field method (MST-SCRF), and allows for a rigorous partition of the total solvation free energy into surface elements. The method gives a complete picture of the hydrophobicity/hydrophilicity of molecules. Present results allow us to expect that the method might provide useful information in drug design and molecular modeling studies. |
Barril,; Aleman,; Orozco,; Luque, Proteins, 32 (1), pp. 67–79, 1998, ISSN: 0887-3585 (Print). @article{Barril1998, title = {Salt bridge interactions: stability of the ionic and neutral complexes in the gas phase, in solution, and in proteins.}, author = { X Barril and C Aleman and M Orozco and F J Luque}, url = {http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0134(19980701)32:1%3C67::AID-PROT8%3E3.0.CO;2-B/abstract}, issn = {0887-3585 (Print)}, year = {1998}, date = {1998-07-01}, journal = {Proteins}, volume = {32}, number = {1}, pages = {67--79}, abstract = {A theoretical study on the stability of the salt bridges in the gas phase, in solution, and in the interior of proteins is presented. The study is mainly focused on the interaction between acetate and methylguanidinium ions, which were used as model compounds for the salt bridge between Asp (Glu) and Arg. Two different solvents (water and chloroform) were used to analyze the effect of varying the dielectric constant of the surrounding media on the salt bridge interaction. Calculations in protein environments were performed by using a set of selected protein crystal structures. In all cases attention was paid to the difference in stability between the ion pair and neutral hydrogen-bonded forms. Comparison of the results determined in the gas phase and in solution allows us to stress the large influence of the environment on the binding process, as well as on the relative stability between the ionic and neutral complexes. The high anisotropy of proteins and the local microenvironment in the interior of proteins make a decisive contribution in modulating the energetics of the salt bridge. In general, the formation of salt bridges in proteins is not particularly favored, with the ion pair structure being preferred over the interaction between neutral species.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A theoretical study on the stability of the salt bridges in the gas phase, in solution, and in the interior of proteins is presented. The study is mainly focused on the interaction between acetate and methylguanidinium ions, which were used as model compounds for the salt bridge between Asp (Glu) and Arg. Two different solvents (water and chloroform) were used to analyze the effect of varying the dielectric constant of the surrounding media on the salt bridge interaction. Calculations in protein environments were performed by using a set of selected protein crystal structures. In all cases attention was paid to the difference in stability between the ion pair and neutral hydrogen-bonded forms. Comparison of the results determined in the gas phase and in solution allows us to stress the large influence of the environment on the binding process, as well as on the relative stability between the ionic and neutral complexes. The high anisotropy of proteins and the local microenvironment in the interior of proteins make a decisive contribution in modulating the energetics of the salt bridge. In general, the formation of salt bridges in proteins is not particularly favored, with the ion pair structure being preferred over the interaction between neutral species. |