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

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Molecular Pharmacology

Background:

• Selective inhibition of cyclin-dependent kinase 8 and cyclin C (CDK8/CycC) is a potential cancer treatment strategy.
• CDK8/CycC inhibition may reduce mitogenic signals in cancer cells with lower toxicity to normal cells.

Purpose of the Study:

• To develop and validate a novel virtual screening protocol for discovering new CDK8/CycC type II ligands.
• To identify drug-like compounds with long residence time and specificity for CDK8/CycC.

Main Methods:

• Analysis of binding thermodynamics for existing ligands using molecular dynamics simulations and VM2 free-energy calculations.
• Substructure-based virtual screening utilizing a novel superposition and single-point energy evaluation method.
• Free-energy calculations and bioassay testing of selected purchasable compounds.

Main Results:

• The urea moiety was identified as a critical structural element in reference ligands.
• The virtual screening protocol accurately predicted the experimental ranking of identified compounds.
• A potent drug-like compound with a K_d of 42.5 nm was discovered, serving as a promising lead for further optimization.

Conclusions:

• The developed virtual screening protocol is an accurate and efficient tool for drug development.
• The study successfully identified novel, potent CDK8/CycC inhibitors.
• This work provides a strong foundation for developing new cancer therapeutics targeting CDK8/CycC.