Discovery of novel inhibitors of CDK2 using docking and physics‐based binding free energy calculation

Abstract 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 IC 50 reaching ~2 μM. 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.