Binding of 13-Amidohuprines to Acetylcholinesterase: Exploring the Ligand-Induced Conformational Change of the Gly117-Gly118 Peptide Bond in the Oxyanion Hole

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• 作者：Pelayo Camps ; Elena Gó ; mez ; Diego Muñ ; oz-Torrero ; Albert Badia ; Maria Victò ; ria Clos ; Carles Curutchet ; Jordi Muñ ; oz-Muriedas ; Francisco Javier Luque
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 16, 2006
• 年：2006
• 卷：49
• 期：23
• 页码：6833 - 6840
• 全文大小：153K
• 年卷期：v.49,no.23(November 16, 2006)
• ISSN：1520-4804

文摘

The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designedto 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 aremore potent human AChE inhibitors than tacrine and (-)-huperzine A, none of them equals the potency ofhuprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118conformational flip induced upon binding of (-)-huperzine A, leading to a similar pattern of interactions asthat formed by the pyridone amido group of (-)-huperzine A. The detrimental effect on the binding affinityrelative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with theligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensurethe preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residuesGly117 and Gly118 play a relevant role in mediating substrate recognition.