R基团筛选技术用于吡啶杂环类mTOR抑制剂的分子设计研究  

Molecular design for pyridine heterocyclic of mTOR inhibitors using R-group search technology

作　　者：刘桦[1] 蒲铃铃[1] 宋海星[1] 杨菁[1] 梁桂兆[2] LIU Hua;PU Ling-ling;SONG Hai-xing;YANG Jing;LIANG Gui-zhao(Chengdu Medical College,Provincial Key Laboratory of Biomedical Experimental Teaching,Chengdu 610050,China;School of Bioengineering,Chongqing University,Key Laboratory of Biorheological Science and Technology,Ministry of Education,Chongqing 400044,China)

机构地区：[1]成都医学院生物医学系,生物医学实验教学省重点实验室,四川成都610050 [2]重庆大学生物工程学院,生物流变科学与技术教育部重点实验室,重庆400044

出　　处：《分子科学学报》2018年第4期331-337,共7页Journal of Molecular Science

基　　金：四川省教育厅资助项目(16ZB0277);国家级大学生创新项目(201413705029)

摘　　要：针对27个吡啶杂环类抑制剂采用Topomer COMFA方法进行了三维定量构效关系分析,新建模型的拟合、交互验证及外部验证的复相关系数分别为r2=0.982,q2=0.857,r2pred=0.829,结果表明模型具有良好的预测能力和可信度.采用基于R基团搜索Topomer Search技术对ZINC数据库进行R基团的虚拟筛选,获得了6个高活性的新抑制剂分子,其预测活性均优于训练集中活性最高分子.运用Surflex-dock分子对接法研究吡啶杂环类抑制剂与mTOR靶点的作用模式.研究结果表明,Topomer search可有效地用于分子设计,结合分子对接结果,新抑制剂分子为mTOR靶向药物设计提供参考.Three-dimensional quantitative structure-activity relationship analysis of 27 pyridine heterocyclic inhibitors was carried out by Topomer COMFA.The new model＇s correlation coefficient of fitting,cross validation and external validation were r2=0.982,q2=0.857,r2 pred=0.829.The results show that the model has good prediction ability and reliability.The R-group was screened from the ZINC database using R-group search technology of Topomer search.6 new inhibitors with high activity were obtained,and their predictive activity was better than that of the highest concentration of template molecules.Study on the mode of action of pyridine heterocyclic inhibitors and mTOR targets by Surflex-dock molecular docking.The results show that Topomer search can be effectively used in molecular design,and the results are consistent with those of molecular docking.The newly designed inhibitors provide reference for the design of mTOR targeting drugs.

关 键 词：Topomer COMFA 三维定量构效关系 Topomer SEARCH mTOR靶点 

分 类 号：O626[理学—有机化学]