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

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Araujo JQ, de Brito MA, Hoelz LV, de Alencastro RB, Castro HC, Rodrigues CR, Albuquerque MG

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

Eur J Med Chem. 2011 Jan;46(1):39-51. doi: 10.1016/j.ejmech.2010.10.009. Epub 2010 Oct 15.

PubMed ID

21074294 [ View in PubMed

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Abstract

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, q(2) = 0.736, r(2) = 0.860) and C-F (N = 47, q(2) = 0.753, r(2) = =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 pIC(50) for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Zanapezil	Acetylcholinesterase	IC 50 (nM)	194.98	N/A	N/A	Details