高等学校化学学报2017，Vol.38Issue(11)：2061-2069,9.DOI:10.7503/cjcu20170237
含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟
Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors
摘要
Abstract
The interaction modes between phosphorus containing pyrimidine cyclin dependent kinase 9 ( CDK9) inhibitors and the protein were studied using the combination of molecular docking and three-dimensional quantitative structure-activity relationships(3D-QSAR). The interaction mode obtained by molecu-lar docking revealed that the molecule conformation, hydrophobic interaction and H-bond, as well as Cys106 played an important role in the binding of phosphorus containing pyrimidines and CDK9. Based on the result of molecular docking, 3D-QSAR models were established by comparative molecular field analysis(CoMFA), comparative molecular similarity indices analysis( CoMSIA) and Topomer CoMFA techniques. With the best CoMSIA-SEH model, the cross-validated value ( Q2 ) was 0. 557, the non-cross-validated value ( R2 ) was 0. 959. The predictive power of the CoMSIA-SEH model was determined from external test sets that were exclu-ded during model development( r2=0. 863) . Ten new compounds were obtained based on the above modeling, and the results of molecular docking and molecular dynamics simulation suggested they could act as potential CDK9 inhibitors, especially compound 64d with more potent inhibitory activity proved by molecular dynamics simulation and binding free energy analysis. It was expected that these results could help establish the binding mechanism between phosphorus containing pyrimidines and CDK9, and provide a valuable reference for future anti-CDK9 drug design.关键词
含磷嘧啶类细胞周期依赖性蛋白激酶抑制剂/分子对接/比较分子力场分析/比较分子相似性指数分析/TopomerCoMFA/分子动力学Key words
Cyclin dependent kinase ( CDK9 ) inhibitor/Surflex-dock/Comparative molecular field analysis (CoMFA)/Comparative molecular similarity indices analysis(CoMSIA)/Topomer CoMFA/Molecular dy-namics分类
化学化工引用本文复制引用
唐光辉,张娅,张玉萍,周朋朋,林治华,王远强..含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟[J].高等学校化学学报,2017,38(11):2061-2069,9.基金项目
国家自然科学基金(批准号:31400667)、重庆市教委科学技术研究项目(批准号:KJ1400932, KJ1500902, KJ1600908)、重庆市基础研究与前沿技术研究项目(批准号: csc2014jcyjA10044, cstc2013jcyjA10019)和重庆高校创新团队建设计划项目(批准号:CXTDX201601031)资助.Supported by the National Natural Science Foundation of China(No.31400667), the Scientific and Technological Research Program of Chongqing Municipal Education Commission, China ( Nos. KJ1400932, KJ1500902, KJ1600908 ) , the Chongqing Research Program of Basic Research and Frontier Technology, China ( Nos. csc2014jcyjA10044, cstc2013jcyjA10019 ) and the Program for Innovation Team Building at Institutions of Higher Education in Chongqing, China(No.CXTDX201601031). （批准号:31400667）
