Discovery of 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine as Novel Cyclin-dependent Kinases 4 and 6 Dual Inhibitors via 3D-QSAR and Molecular Simulation  

作　　者：FU Le ZHAO Li-Nan GUO Hong-Mei YU Na QUAN Wen-Xuan CHEN Yi SHU Mao WANG Rui LIN Zhi-Hua 付乐;赵丽楠;郭红梅;余娜;全纹萱;陈义;舒茂;王锐;林治华(School of Pharmacy and Bioengineering,Chongqing University of Technology,Chongqing 400054,China;Qianjiang Central Hospital of Chongqing,Chongqing 409099,China)

机构地区：[1]School of Pharmacy and Bioengineering,Chongqing University of Technology,Chongqing 400054,China [2]Qianjiang Central Hospital of Chongqing,Chongqing 409099,China

出　　处：《Chinese Journal of Structural Chemistry》2022年第3期108-124,I0010,共18页结构化学（英文）

基　　金：supported by the key project of Chongqing Natural Science Foundation (cstc2015jcyj BX0080)

摘　　要：Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis fields(CoMSIA)was implemented on 52 dual CDK4/6 inhibitors.As a result,we obtained a pretty good 3D-QSAR model,which is CoMFACDK4 with q2 to be 0.543 and r^(2) to be 0.967;CoMSIACDK4 with q2 being 0.518 and r^(2) being 0.937;CoMFACDK6 with q2 to be 0.624 and r^(2) to be 0.984;CoMSIACDK6 with q2 being 0.584 and r^(2) being 0.975.Molecular docking confirmed the important residues for interactions.Molecular dynamics simulation further confirmed binding affinity with key residues of protein,such as Lys22,Lys35,Val96 for CDK4 and Lys43,His100,Val101 for CDK6 at the active sites.Then these results offered new directions to explore new inhibitors of CDK4/6.Finally,we designed 10 novel compounds with promising expected activity and ADME/T properties,and provided referable synthetic routes.

关 键 词：cyclin-dependent kinases 4 and 6 dual inhibitors 3D-QSAR drug design molecular simulation 

分 类 号：TQ460.1[化学工程—制药化工]