Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 99, Issue 5, Pages 662-673Publisher
WILEY
DOI: 10.1111/cbdd.14027
Keywords
binding free energy calculation; CDK2; inhibitory activity; virtual screening
Funding
- Ministry of Science and Technology of China [2016YFA0501700]
- National Natural Science Foundation of China [91753103, 31700646]
- Natural Science Foundation of Shanghai [19ZR1473600]
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This study discovered novel inhibitors of CDK2 using molecular docking and physics-based binding free energy calculation method AS-IE. The decomposition of binding free energy revealed key protein-ligand interactions and provided a good example for drug design.
Cyclin-dependent kinase (CDK) is a serine/threonine protein kinase family that cooperates with cyclin and plays an important role in the regulation of cell cycle. Cyclin-dependent kinase 2 is an important member of the CDK family and holds great promise as an anti-cancer drug target. In this study, we used molecular docking and physics-based binding free energy calculation method AS-IE that explicitly calculated protein-ligand binding entropy to discover novel inhibitors of CDK2. A total of 17 inhibitors were discovered with the best IC50 reaching similar to 2 mu M. Decomposition of the binding free energy using AS-IE reveals key protein-ligand interactions that determines the activity. These results provided a good example of drug design using physics-based free energy calculation method such as AS-IE and the novel compounds offered a good start point for further development of CDK2 inhibitors.
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