Discovery of Potential Inhibitors of CDK1 by Integrating Pharmacophore-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation Studies, and Evaluation of Their Inhibitory Activity

The ability of CDK1 to compensate for the absence of other cell cycle CDKs poses a great challenge to treat cancers that overexpress these proteins. Despite several studies focusing on the area, there are no FDA-approved drugs selectively targeting CDK1. Here, the study aimed to develop potential CDK1 selective inhibitors through drug repurposing and leveraging the structural insights provided by the hit molecules generated. Approximately 280,000 compounds from DrugBank, Selleckchem, Otava and an in-house library were screened initially based on fit values using 3D QSAR pharmacophores built for CDK1 and subsequently through Lipinski, ADMET, and TOPKAT filters. 10,310 hits were investigated for docking into the binding site of CDK1 determined using the crystal structure of human CDK1 in complex with NU6102. The best 55 hits with better docking scores were further analyzed, and 12 hits were selected for 100 ns MD simulations followed by binding energy calculations using the MM-PBSA method. Finally, 10 hit molecules were tested in an <i>in vitro</i> CDK1 Kinase inhibition assay. Out of these, 3 hits showed significant CDK1 inhibitory potential with IC₅₀ < 5 μM. These results indicate these compounds can be used to develop subtype-selective CDK1 inhibitors with better efficacy and reduced toxicities in the future.