Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE)

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• 作者：Jocley Queiroz Araú ; jo ; Monique Araú ; jo de Brito ; Lucas Villas Bô ; as Hoelz ; Ricardo Bicca de Alencastro ; Helena Carla Castro ; Carlos Rangel Rodrigues ; Magaly Gir&#xe3 ; o Albuquerque
• 关键词：RD-3D-QSAR ; Benzylpiperidine ; Acetylcholinesterase ; Alzheimer disease ; Molecular modeling
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：46
• 期：1
• 页码：39-51
• 全文大小：1660 K

文摘

Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A–F (N = 47, q² = 0.736, r² = 0.860) and C–F (N = 47, q² = 0.753, r² = =0.900) were developed and validated by a combined GA-PLS approach, available in WOLF. Residues of the aromatic gorge (Tyr341 and Trp439) and catalytic triad (His447) are related to both equations showing the consistency of these models with the SAR. Based on those models we have proposed four new benzylpiperidine derivatives and predicted the pIC₅₀ for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor.