Binding of 13-amidohuprines to acetylcholinesterase: Exploring the ligand-induced conformational change of the Gly117-Gly118 peptide bond in the oxyanion hole

TitleBinding of 13-amidohuprines to acetylcholinesterase: Exploring the ligand-induced conformational change of the Gly117-Gly118 peptide bond in the oxyanion hole
Publication TypeJournal Article
Year of Publication2006
AuthorsCamps, P, Gomez E, Munoz-Torrero D, Badia A, Clos M V, Curutchet C, Munoz-Muriedas J, Luque FJ
JournalJournal of Medicinal Chemistry
Volume49
Issue23
Pagination6833 - 6840
Date Published2006
ISBN Number0022-2623
Keywordsalzheimers-disease, catalytic power, empirical scoring function, free-energies, huprine-x, in-vitro pharmacology, inhibitors, molecular-dynamics, potential interest, tacrine-huperzine
AbstractThe 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.