Discovery of Potential\nInhibitors of CDK1 by Integrating\nPharmacophore-Based Virtual Screening, Molecular Docking, Molecular\nDynamics Simulation Studies, and Evaluation of Their Inhibitory Activity

The ability of CDK1\nto compensate for the absence of\nother cell\ncycle CDKs poses a great challenge to treat cancers that overexpress\nthese proteins. Despite several studies focusing on the area, there\nare no FDA-approved drugs selectively targeting CDK1. Here, the study\naimed to develop potential CDK1 selective inhibitors through drug\nrepurposing and leveraging the structural insights provided by the\nhit molecules generated. Approximately 280,000 compounds from DrugBank,\nSelleckchem, Otava and an in-house library were screened initially\nbased on fit values using 3D QSAR pharmacophores built for CDK1 and\nsubsequently through Lipinski, ADMET, and TOPKAT filters. 10,310 hits\nwere investigated for docking into the binding site of CDK1 determined\nusing the crystal structure of human CDK1 in complex with NU6102.\nThe best 55 hits with better docking scores were further analyzed,\nand 12 hits were selected for 100 ns MD simulations followed by binding\nenergy calculations using the MM-PBSA method. Finally, 10 hit molecules\nwere tested in an <i>in vitro</i> CDK1 Kinase inhibition\nassay. Out of these, 3 hits showed significant CDK1 inhibitory potential\nwith IC<sub>50</sub> < 5 μM. These results indicate these\ncompounds can be used to develop subtype-selective CDK1 inhibitors\nwith better efficacy and reduced toxicities in the future.