Citation: Le FU, Li-Nan ZHAO, Hong-Mei GUO, Na YU, Wen-Xuan QUAN, Yi CHEN, Mao SHU, Rui WANG, Zhi-Hua LIN. 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[J]. Chinese Journal of Structural Chemistry, ;2022, 41(3): 220310. doi: 10.14102/j.cnki.0254-5861.2011-3270 shu

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

Le FU ^{a, b} ,
Li-Nan ZHAO ^a ,
Hong-Mei GUO ^a ,
Na YU ^a ,
Wen-Xuan QUAN ^a ,
Yi CHEN ^a ,
Mao SHU ^a,, ,
Rui WANG ^a ,
Zhi-Hua LIN ^a,,

a.
School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
b.
Qianjiang Central Hospital of Chongqing, Chongqing 409099, China

Corresponding author: Mao SHU, shumao@cqut.edu.cn Zhi-Hua LIN, zhlin@cqut.edu.cn
Received Date: 27 May 2021
Accepted Date: 27 July 2021

Fund Project: the key project of Chongqing Natural Science Foundation cstc2015jcyjBX0080

Figures(12)

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 analysis (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 CoMFA_CDK4 with q² to be 0.543 and r² to be 0.967; CoMSIA_CDK4 with q² being 0.518 and r² being 0.937; CoMFA_CDK6 with q² to be 0.624 and r² to be 0.984; CoMSIA_CDK6 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.
- cyclin-dependent kinases 4 and 6 dual inhibitors,
- 3D-QSAR,
- drug design,
- molecular simulation
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