%0 Journal Article %J Journal of Medicinal Chemistry %D 2006 %T Binding of 13-amidohuprines to acetylcholinesterase: Exploring the ligand-induced conformational change of the Gly117-Gly118 peptide bond in the oxyanion hole %A Camps, Pelayo %A Gomez, Elena %A Munoz-Torrero, Diego %A Badia, Albert %A Clos, Maria Victoria %A Curutchet, Carles %A Munoz-Muriedas, Jordi %A F. J. Luque %K alzheimers-disease %K catalytic power %K empirical scoring function %K free-energies %K huprine-x %K in-vitro pharmacology %K inhibitors %K molecular-dynamics %K potential interest %K tacrine-huperzine %N 23 %P 6833 - 6840 %V 49 %X The acetylcholinesterase ( AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designed to enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (-)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives are more potent human AChE inhibitors than tacrine and (-)- huperzine A, none of them equals the potency of huprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118 conformational flip induced upon binding of (-)- huperzine A, leading to a similar pattern of interactions as that formed by the pyridone amido group of (-)- huperzine A. The detrimental effect on the binding affinity relative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with the ligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensure the preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residues Gly117 and Gly118 play a relevant role in mediating substrate recognition. %8 2006 %@ 0022-2623