噻嗪类11β-羟类固醇脱氢酶抑制药三维定量构效关系研究

3D-QSAR of Thiazide 11β-Hydroxyl Steroid Dehydrogenase Inhibitors

目的:通过构建噻嗪类11β-羟类固醇脱氢酶(11β-HSD)抑制药的三维定量构效关系(3D-QSAR)模型,用于其结构改造及发现具有更高生物活性的11β-HSD抑制药。方法:基于骨架叠合的模式,采用比较分子力场分析(CoMFA)的方法,构建噻嗪类衍生物定量构效关系模型,并用分子对接的方法对已构建的3D-QSAR模型进行验证。结果:得到了高精度的11β-HSD抑制药的3D-QSAR模型(CoMFA:q^2=0.346,r^2=0.850;其中q^2为交叉验证系数,r^2为非交叉验证系数)。结论:本文构建的3D-QSAR模型可为11β-HSD抑制药骨架各个位点的化学修饰,实施定向合理设计,为开发新型抗2型糖尿病药物提供理论基础。

Objective： To establish a three-dimensional quantitative structure-activity relationship （3D-QSAR） model for thiazide 11β-hydroxy steroid dehydrogenase （HSD） inhibitors in order to perform structure modification and find thiazide 11β-HSD inhibitors with more activity. Methods： The 3D-QSAR model of thiazine derivatives was construcied by the method of comparative molecular force field analysis, and the model was validated by using a molecular docking method. Results： An accurate 3D-QSAR model of 11β- HSD inhibitors was obtained （ CoMFA ： q2 = 0. 346, r2 = 0. 850, where q2 was the cross-validation coefficient and r2 was the non-cross validation coefficient）. Conclusion： The results provide important theoretical basis for the rational design of novel thiazide 11β-HSD inhibitors. relationship; Comparative force field analysis; Molecular docking