Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Química (IQ), Programa de Pós-Graduação em Química (PPGQu), Laboratório de Modelagem Molecular (LabMMol), Rio de Janeiro, RJ, Brazil.
Eur J Med Chem. 2011 Jan;46(1):39-51. doi: 10.1016/j.ejmech.2010.10.009. Epub 2010 Oct 15.
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.
乙酰胆碱抑制剂 (AChEIs) 目前被认为是治疗阿尔茨海默病的潜在药物。在这项工作中，我们基于一系列 60 种人乙酰胆碱酯酶的苄基哌啶抑制剂，开发了一种基于受体的 3D-QSAR（RD-3D-QSAR）模型，以支持新的 AChEIs 的设计。通过 GA-PLS 组合方法开发和验证了最好的两个模型 A-F（N=47，q²=0.736，r²=0.860）和 C-F（N=47，q²=0.753，r²=0.900），该方法可在 WOLF 中使用。芳香沟（Tyr341 和 Trp439）和催化三联体（His447）的残基与这两个方程有关，表明这些模型与 SAR 一致。基于这些模型，我们提出了四个新的苄基哌啶衍生物，并预测了每个分子的 pIC（50）。苄基哌啶衍生物 IIa 的良好预测效力表明它是一种有潜力的新型 HuAChE 抑制剂候选物。
