An Effective Reaction‐Based Virtual Screening Method to Discover New CDK8 Ligands

Cyclin Dependent Kinase 8 (CDK8) is a valuable drug target for cancer suppression. Through an effective reaction-based virtual screening method consisting of pharmacophore modeling, Scifinder database searches, and energy evaluations, a number of new type II CDK8 ligands were discovered with comparable or better binding free energies than the ones reported in literature. In this method, a pharmacophore model, derived from seven crystal structures of CDK8 and type II ligands, was able to catch the key interactions for ligands binding at the ATP binding site of CDK8. This model then was used to screen the results from Scifinder database searches that apply chemical reaction rules in the search cycles, and the output compounds were evaluated and ranked first by a fast energy estimation method and then by the VM2 free energy calculation method. Among the top discovered ligands, three have lower K_d values against CDK8 than a potent reference ligand, and compound F (3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-(8-hydroxynaphthalen-1-yl)urea) is the most potent one with an K_d value of 7.5 nM. Compound F has a relatively small molecular structure, receives both strong van der Waals energy and optimized overall electrostatic energy when binding with CDK8, and deserves to be a promising lead compound for further development. This effective virtual screening method and the novel compounds found in this work have implications for CDK8 drug discovery.