@article {596,
	title = {Binding of 13-amidohuprines to acetylcholinesterase: Exploring the ligand-induced conformational change of the Gly117-Gly118 peptide bond in the oxyanion hole},
	journal = {Journal of Medicinal Chemistry},
	volume = {49},
	year = {2006},
	month = {2006},
	pages = {6833 - 6840},
	abstract = {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.},
	keywords = {alzheimers-disease, catalytic   power, empirical scoring function, free-energies, huprine-x, in-vitro pharmacology, inhibitors, molecular-dynamics, potential interest, tacrine-huperzine},
	isbn = {0022-2623},
	author = {Camps, Pelayo and Gomez, Elena and Munoz-Torrero, Diego and Badia, Albert and Clos, Maria Victoria and Curutchet, Carles and Munoz-Muriedas, Jordi and F. J. Luque}
}
