Binding Mechanism of Inhibitors to CDK6 Deciphered by Multiple Independent Molecular Dynamics Simulations and Free Energy Predictions.

Cyclin-dependent kinase 6 (CDK6) has been identified as a potential drug target in various types of cancers. In our current study, multiple independent molecular dynamics simulations of four separate replicates and computations of binding free energies are carried out to decipher the binding mechanisms of three inhibitors, LQQ, 6ZV, and 0RS, to CDK6. The dynamic analyses indicate that the presence of inhibitors influences conformational alterations, motion modes, and the internal dynamics of CDK6. Binding free energies computed using the molecular mechanics generalized Born surface area (MM-GBSA) approach with four GB models demonstrate that hydrophobic interactions play essential roles in inhibitor-CDK6 binding. The computations of residue-based free energy decomposition verify that the side chains of residues I19, K29, M54, P55, F98, H100, and L152 significantly contribute to inhibitor-CDK6 binding, revealing the critical interaction sites of inhibitors for CDK6. The information revealed in our current study can provide theoretical aids for development of potent inhibitors targeting the CDK family.