Roscovitine derivative optimization via molecular dynamics reveals potent and selective CDK5 binders

CDK5 is an atypical member of the CDKs family that is not directly involved in cell cycle regulation but has a very relevant role in promoting DNA damage response and immune response evasion in cancer. Its action in these tasks conflicts with those of other CDKs, namely CDK4 and CDK6. It is therefore relevant to find small molecule catalytic inhibitors that could be selective for CDK5. Roscovitine has been found to inhibit CDK5 more efficiently than CDK4 and CDK6 in vitro, appearing to be an ideal initial candidate. We analyzed the structural interaction of Roscovitine and some of its derivatives with different CDKs by molecular docking, dynamics and free energy calculation to identify those showing a high affinity for CDK5 (and eventually CDK2) accompanied by optimal discrimination against CDK4/CDK6 and to derive chemical clues to eventually produce other, more selective and efficient compounds.