基于他克林的乙酰胆碱酯酶抑制剂的3D-QSAR研究及虚拟筛选

Virtual screening and 3D-QSAR study based on acetylcholinesterase inhibitors of tacrine

本文通过对58个他克林派生物乙酰胆碱酯酶抑制剂分子进行建模分析，研究其结构与活性的关系，并通过虚拟筛选方法获得一系列潜在AChE抑制剂双位点分子。首先将一系列他克林二联体化合物与AChE晶体结构对接，获得化合物的活性构象，以此进行建模分析，建立结构与活性之间的三维定量构效关系。所得模型CoMFA、CoMSIA、TopomerCoMFA的交叉验证系数分别为0.510、0.702、0.571，非交叉验证系数为0.998、0.988、0.794，测试集r2pred为0.750、0.742、0.766，所得模型具有良好的预测性，由此可以为设计高活性的新分子提供理论基础。然后，使用Topomer search对ZINC数据库中的125909分子进行虚拟筛选，得到891个具有潜在AChE抑制活性的分子。最后，对这891个分子进行分子对接，观察分子与晶体结构的结合情况，筛选得到66个具有高选择性的双位点AChE抑制剂分子。

In this study,58 acetylcholinesterase（AChE）inhibitors were studied for the relationship between structure and activity.A series of potential dual binding AChE inhibitors were obtained by virtual screening.First,bioactive conformations were generated by docking a series of Tacrine Dimers Analogs with AChE crystal structure.3D quantitative structure activity relationship （3D-QSAR） models were developed for AChE inhibitors using modeling analysis.The cross-validated coefficient q 2 values of 3D-QASR（CoMFA, CoMSIA,and TopomerCoMFA ） methods were 0.510,0.702,and 0.571,the non-cross-validated r 2 values were 0.998,0.988, 0.794,r2pred were 0.826,0.776,0.766 and all these models have good predictability ,and provide theoretical basis for designing new high activity molecules.Then 125,909 molecules obtained from ZINC database were virtual screened by using Topomer search ,891 molecules with potential AChE inhibitory activity were obtained.Finally,the combination of 891 molecules and AChE crystal struc-ture were confirmed by using molecular docking ,66 molecules endowed with dual binding were obtained ,which have high selectivity of AChE inhibitory activity.