Journal
NATURE CHEMICAL BIOLOGY
Volume 10, Issue 12, Pages 1066-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1666
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Funding
- US National Institutes of Health (NIH) [GM59957, GM71896]
- Ministsre de la Recherche et de la Technologie
- Institut national de la sante et de la recherche medicale [U1071]
- Institut National de la Recherche Agronomique [USC-2018]
- Centre Hospitalier Regional Universitaire de Clermont-Ferrand, France
- EMBO long-term fellowship [ALTF 1121-2011]
- Sandler Foundation
- California Tobacco-Related Disease Research Program [19FT-0091]
- Howard Hughes Medical Institute Predoctoral Fellowship
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Chemical probes that form a covalent bond with a protein target often show enhanced selectivity, potency and utility for biological studies. Despite these advantages, protein-reactive compounds are usually avoided in high-throughput screening campaigns. Here we describe a general method (DOCKovalent) for screening large virtual libraries of electrophilic small molecules. We apply this method prospectively to discover reversible covalent fragments that target distinct protein nucleophiles, including the catalytic serine of AmpC beta- lactamase and noncatalytic cysteines in RSK2, MSK1 and JAK3 kinases. We identify submicromolar to low-nanomolar hits with high ligand efficiency, cellular activity and selectivity, including what are to our knowledge the first reported reversible covalent inhibitors of JAK3. Crystal structures of inhibitor complexes with AmpC and RSK2 confirm the docking predictions and guide further optimization. As covalent virtual screening may have broad utility for the rapid discovery of chemical probes, we have made the method freely available through an automated web server (http://covalent.docking.org/).
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