Stable H-bond networks are crucial for selective CDK4 inhibition revealed from comprehensive in silico investigation

Zhigang Zhang; Baichun Hu; Johnson Joseph; Ying Wang; Jianping Mao; Haoyu Zhang; Qi Ma; Yaoliang Zhang; Jian Wang

doi:10.1016/j.compbiolchem.2022.107699

Stable H-bond networks are crucial for selective CDK4 inhibition revealed from comprehensive in silico investigation

Comput Biol Chem. 2022 Aug:99:107699. doi: 10.1016/j.compbiolchem.2022.107699. Epub 2022 May 24.

Authors

Zhigang Zhang¹, Baichun Hu¹, Johnson Joseph¹, Ying Wang², Jianping Mao², Haoyu Zhang¹, Qi Ma¹, Yaoliang Zhang¹, Jian Wang³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
³ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: jianwang@syphu.edu.cn.

PMID: 35667300
DOI: 10.1016/j.compbiolchem.2022.107699

Abstract

CDK1 and CDK4 are highly similar isoforms but with apparently diverse cellular functions, which makes it fundamental to discover selective CDK4 inhibitors that could accurately control the process of cell cycle of the specific organization so as to restore normal physiological state. In current research, interaction modes of CDK1 and CDK4 inhibitors were investigated through combined in silico strategies to elucidate the selectivity mechanism against CDK4 over CDK1, revealing that H-bond networks formed with key amino acids such as LYS33 and LEU83 of CDK1 and VAL93 of CDK4 are crucial for CDK4 selective inhibition, which would provide a theoretical basis for the design of selective CDK4 inhibitors.

Keywords: Binding patterns; CDK inhibitor; In silico; Molecular dynamics simulation; Selective inhibition.

MeSH terms

Cyclin-Dependent Kinase 4*

Substances

Cyclin-Dependent Kinase 4