Targeting Cyclin-Dependent Kinase 12 (CDK12) for Cancer Therapy: Structure-Based Discovery of Two Novel CDK12 Inhibitors <i>In Silico</i> Using Integrated Bioinformatics

Cyclin-dependent kinase 12 (CDK12) is thought to play an important role in cancer biology pathogenesis and development. Novel, selective, safe, and effective CDK12 inhibitors are actively sought after in drug discovery and clinical development. We report here the structure-based discovery of two novel CDK12 inhibitors using integrated molecular docking, simulation, and molecular mechanics Poisson-Boltzmann surface area methods. We performed a virtual high-throughput screening of potential inhibitors sourced from the ZINC database, which contains ∼90,000 molecules. Various filters were applied to separate bioactive molecules using Lipinski's rule of five, Absorption, Distribution, Metabolism, Excretion, and Toxicity properties, Ghose filters, and Pan-assay interference compound filters. Furthermore, the elucidated compounds were subjected to molecular docking to evaluate their binding toward the target. Interaction analysis of the selected compounds showed favorable interactions with the active site pocket residues of CDK12 for ZINC 02096057 and ZINC 02094702. These two compounds modulate both the active and adenosine triphosphate (ATP)-binding sites of the target CDK12, inhibiting its biological activity. Moreover, flavopiridol, a known inhibitor of CDK12, was used to cross-check with the selected ligands to validate our findings. Molecular dynamics simulation was performed at 500 ns to evaluate the dynamics of each atom in the system. Finally, we suggest that ZINC 02096057 and ZINC 02094702 offer prospects as novel inhibitors of CDK12, which warrant further <i>in vitro</i> and <i>in vivo</i> studies. Cancer therapeutics specifically, and drug discovery more generally, stand to benefit from novel molecular leads for CDK12 inhibition.