Identification of bioactive natural products as potential inhibitors of cyclin-dependent kinase-8: A virtual screening study for anticancer therapeutics

Abstract Cyclin-dependent kinase 8 (CDK8) is one of the members of the cyclin-dependent kinase family. It is highly expressed in various diseases and is a potent therapeutic target for developing anticancer drugs. We performed a virtual screening using the ZINC library to elucidate its potential inhibitors. We initiated our study by performing virtual screening using the ZINC library, which comprises approximately 90,000 compounds and applied Lipinski's rule of five, ADMET properties and PAINS filter to eliminate promiscuous binders. Subsequently, the filtered compounds underwent molecular docking to predict their binding affinity and interactions with the CDK8 protein. Interaction analysis was carried out to elucidate the interaction mechanism of the screened hits with binding pockets of the CDK8. Finally, ZINC02152165, ZINC04236005, and ZINC02134595 were selected with appreciable specificity and affinity with CDK8. To explore the conformational dynamics of CDK8 with the elucidated compounds, an all-atom molecular dynamic (MD) simulation followed by essential dynamics was performed for 200 ns. Overall, the result indicated that ZINC02152165, ZINC04236005, and ZINC02134595 could be exploited as potential leads in therapeutic development. The comprehensive computational approach provides valuable insights into the molecular mechanisms underlying CDK8 inhibition and paves the way for further experimental validation and drug development efforts.