3D-QSAR和分子对接研究吲哚咔唑类细胞周期蛋白激酶抑制剂的选择性

细胞周期蛋白激酶(cyclin-dependent kinases, CDKs)是近年来治疗肿瘤的重要靶标. 由于大多数激酶ATP结合位点的保守性, CDK选择性激酶抑制剂的开发成为当前的研发难点和热点. 针对吲哚咔唑类CDK抑制剂, 我们采用比较分子力场分析方法(CoMFA)建立了CDK2-QSAR(quantitative structure-activity relationship)和CDK4-QSSR(quantitative structure-selectivity relationship)模型. 所建模型的交叉验证系数q2分别为0.722和0.703; 非交叉验证系数r2分别为0.977和0.946, 表明其具有较好的预测能力. 同时, 用分子对接的方法分析了这类化合物与CDK4同源模建结构的作用模式, 根据这两个模型发现, 吲哚咔唑类化合物的R5和R6位长链取代对CDK4的选择性具有一定的影响, 而且结合其作用模式比较合理地解释了这类抑制剂的选择性原因, 这对CDKs的选择性研究具有一定的指导意义.

3D-QSAR and Molecular Docking Study on Selectivity of Indolocarbazole Series as Cyclin-Dependent Kinase Inhibitors

Cyclin-dependent kinases (CDKs) have appeared as important anti-tumor targets over the years. Given that large numbers of kinases share conserved ATP binding pockets, the identification of a particular CDK inhibitor is currently under active investigation. This study was concerned with the design of CDK inhibitors with enhanced inhibitory potencies and subtype specificity. Specifically, CDK2-QSAR(quantitative structure-activity relationship) and CDK4-QSSR(quantitative structure-selectivity relationship) CoMFA(comparative molecular field analysis) studies were carried out on indolocarbazole derivatives as CDK inhibitors. The developed models have a cross validated correlation co-efficient q2 of 0.722 and 0.703 and a non-cross validated correlation co-efficient r2 of 0.977 and 0.946, respectively, which thus show a great predictive capability. These models suggested that side chain substituents of R5 and R6 of indolocarbazoles are expected to improve the selectivity of the molecules. CoMFA contour maps and the presumed binding modes provide an interpretable explanation of selectivity and this will guide further research.