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

发布时间：2018-08-17 18:18

【摘要】：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r_(pred)~2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。
[Abstract]:In this paper, 58 bioacetylcholinesterase inhibitor molecules of tacrine were modeled and analyzed to study the relationship between their structure and activity, and a series of potential double site AChE inhibitor molecules were obtained by virtual screening method. At first, a series of tacklin dimer compounds were connected with AChE crystal structure to obtain the active conformation of the compounds, and the three-dimensional quantitative structure-activity relationship between the structure and activity was established by modeling and analyzing. The cross validation coefficients of the model are 0.510 / 0.702 / 0.571and the non-cross-validation coefficients are 0.9980.988/ 0.794 and 0.7500.742/ 0.766respectively. The model has good predictability, which can provide a theoretical basis for the design of new molecules with high activity. Then, 125909 molecules in ZINC database were screened by Topomer search, and 891 molecules with potential AChE inhibitory activity were obtained. Finally, the molecular docking of the 891 molecules was carried out, and the binding between the molecules and the crystal structure was observed, and 66 highly selective two-site AChE inhibitor molecules were obtained.
【作者单位】：首都师范大学化学系;
【基金】：北京市教委项目(KM201310028007)资助北京市中青年骨干教师项目(PHR201108146)资助
【分类号】：R749.16

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