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
• 来源期刊: 结构化学
• 年，卷（期）: 2022,（3）
• 页码范围: 108-124
• 页数: 17页
• 语种: 英文
• DOI: 10.14102/j.cnki.0254-5861.2011-3270

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 r2 to be 0.967;CoMSIACDK4 with q2 being 0.518 and r2 being 0.937;CoMFAcDK6 with q2 to be 0.624 and r2 to be 0.984;CoMSIACDK6 with q2 being 0.584 and r2 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.