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

Abstract

Selective inhibition of Cyclin-dependent kinase 8 and cyclin C (CDK8/CycC) has been suggested as a promising strategy for reducing mitogenic signals in cancer cells with reduced toxic effects on normal cells. We developed a novel virtual screening protocol for drug development and applied it to discovering new CDK8/CycC type II ligands, which is likely to achieve long residence time and specificity. We first analyzed 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 bio-assay testing. The ranking from the experimental result is completely consistent with the predicted rankings. A potent drug-like compound has a Kd value of 42.5 nM, which is comparable to the most potent reference ligands and 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.

Super-Enhancers in the Regulation of Gene Transcription: General Aspects and Antitumor Targets

“…Compounds belonging to various chemical classes acting as a platform for the proposed pharmacological blockers of CDK8/19 kinase activity and the so-called degraders for complete elimination of these proteins (overcoming of the kinase-independent function) are being intensively studied [ 68 , 69 ]. The issues related to inhibitor selectivity have been discussed in reviews and original studies [ 53 , 70 , 71 , 72 , 73 ].…”

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry

“…Recently, Chen and coworkers [ 28 ] implemented a novel virtual screening protocol for drug development and applied it to the discovery of new CDK8/CycC type II ligands, starting from the pyrazolyl-ureas previously reported by Schneider et al [ 27 ]. The authors first analyzed the thermodynamic binding of the ligands using molecular dynamics simulations and a free-energy calculation method, then extended the key binding information to assist virtual screening.…”

Open Medicinal Chemistry

“…(https://onlinelibrary.wiley.com/doi/10.1002/cmdc.201800559). Now, https://chemrxiv.org/ has made it even easier for authors to submit their preprint article to ChemMedChem or any of the ChemPubSoc Europe journals. The “Direct Journal Transfer” feature at ChemRxiv streamlines the submission of research articles for peer review in their partner journals…”