Discovery of CDK8/CycC Ligands with a New Virtual Screening Tool

• Published in: ChemMedChem 2019-01, Vol.14 (1), p.107-118
• Main Authors: Chen, Wei, Ren, Xiaodong, Chang, Chia‐en A.
• Format: Article
• Language: English
• Subjects: Binding; binding affinity; Bioassays; Cancer; compound fragments; computer simulations; Cyclin C; Cyclin C - antagonists & inhibitors; Cyclin C - metabolism; Cyclin-Dependent Kinase 8 - antagonists & inhibitors; Cyclin-Dependent Kinase 8 - metabolism; Dose-Response Relationship, Drug; Drug development; Drug Discovery - methods; Drug Evaluation, Preclinical - methods; Humans; in silico screening; kinetics; Ligands; Mathematical analysis; Molecular dynamics; Molecular Structure; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Screening; Structure-Activity Relationship; structure-based drug design; Substructures; Superposition (mathematics); Thermodynamics; Toxicity; Urea; Ureas
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800559

Selective inhibition of cyclin‐dependent kinase 8 and cyclin C (CDK8/CycC) has been suggested as a promising strategy for decreasing mitogenic signals in cancer cells with reduced toxicity toward normal cells. We developed a novel virtual screening protocol for drug development and applied it to the discovery of new CDK8/CycC type II ligands, which is likely to achieve long residence time and specificity. We first analyzed the binding thermodynamics of 11 published pyrazolourea ligands using molecular dynamics simulations and a free‐energy calculation method, VM2, and extracted the key binding information to assist virtual screening. The urea moiety was found to be the critical structural contributor of the reference ligands. Starting with the urea moiety, we conducted substructure‐based searches with our newly developed superposition and single‐point energy evaluation method, followed by free‐energy calculations, and singled out three purchasable compounds for bioassay testing. The ranking from the experimental results is completely consistent with the predicted rankings. A potent drug‐like compound was found to have a Kd value of 42.5 nm, which is similar to those of the most potent reference ligands; this provided a good starting point for further improvement. This study shows that our novel virtual screening protocol is an accurate and efficient tool for drug development. Streamlined compound search: A potent drug‐like compound with CDK8/CycC affinity identified by our novel virtual screening tool has a Kd value of 42.5 nm. Our work first analyzed the binding thermodynamics of 11 published pyrazolourea ligands using MD simulations and a free‐energy calculation method, VM2. A key urea moiety was selected for substructure‐based searches with our newly developed superposition and single‐point energy evaluation method, followed by free‐energy calculations, thus singling out purchasable compounds for bioassay testing.