Kinase-Bench: Comprehensive Benchmarking Tools and Guidance for Achieving Selectivity in Kinase Drug Discovery.

Abstract

Developing selective kinase inhibitors remains a formidable challenge in drug discovery because of the highly conserved structural information on adenosine triphosphate (ATP) binding sites across the kinase family. Tailoring docking protocols to identify promising kinase inhibitor candidates for optimization has long been a substantial obstacle to drug discovery. Therefore, we introduced "Kinase-Bench," a pioneering benchmark suite designed for an advanced virtual screen, to improve the selectivity and efficacy of kinase inhibitors. Our comprehensive data set includes 6875 selective ligands and 422,799 decoys for 75 kinases, using extensive bioactivity and structural data from the ChEMBL database and decoys generated by the Directory of Useful Decoys-Enhanced version. Our benchmarking sets and retrospective case studies were designed to provide useful guidance in discovering selective kinase inhibitors. We employed a Glide High-Throughput Virtual Screen and Standard Precision complemented by three scoring functions and customized protein-ligand interaction filters that target specific kinase residue interactions. These innovations were successfully implemented in our virtual screen efforts targeting JAK1 inhibitors, achieving selectivity against its family member, TYK2. Consequently, we identified novel potential hits: Compound 2 (JAK1 IC₅₀: 980.5 nM, TYK2 IC₅₀: 4.5 μM) and the approved pan-AKT inhibitor Capivasertib (JAK1 IC₅₀: 275.9 nM, TYK2 IC₅₀: 10.9 μM). Using the Kinase-Bench protocol, both compounds demonstrated substantial JAK1 selectivity, making them strong candidates for further investigation. Our pharmaceutical results underscore the utility of tailored virtual screen protocols in identifying selective kinase inhibitors with substantial implications for rational drug design. Kinase-Bench offers a robust toolset for selective kinase drug discovery with the potential to effectively guide future therapeutic strategies effectively.