Discovery of New CDK8 ligands with a Novel Virtual Drug Screening Tool

Abstract Selective inhibition of CDK8 could be a promising strategy for reducing mitogenic signals in cancer cells with reduced toxic effects on normal cells. As compared with type I ligands, binding of a type II compound often achieves longer residence time. We developed a novel virtual drug screening package which takes advantage of two energy evaluation methods: Superposition and Single-Point Energy Evaluation, and VM2 free energy calculation, and applied it to the discovery of new CDK8 type II ligands. In this research we analyzed binding thermodynamics of 11 published CDK8 type II ligands, and extracted the key binding information to assist virtual drug screening for new ligands. The free energy and MD calculations on the reference CDK8-ligand complexes revealed the important factors in the binding. The urea moiety was found to be the critical structural contributor of the reference ligands. Starting with the urea moiety we implemented virtual drug screening and singled out three compounds for bio-assay testing. The ranking from the experimental result for the three compounds is completely consistent with the predicted rankings by both energy evaluation methods. A potent drug-like compound was discovered to have a K d value of 42.5 nM with CDK8, which is comparable to the most potent reference ligands and provided a good starting point to design and synthesize a series of highly selective and potent CDK8 ligands. Therefore, our novel virtual drug screening package is accurate and efficient enough to be used in drug design projects. We believe this work has significant impact to the field of drug discovery.