Covalent Docking of Large Libraries for the Discovery of Chemical Probes

By Nir London, Randy M. Miller, Shyam Krishnan, K. Uchida, John J. Irwin, O. Eidam, L. Gibold, Peter Cimermancic, R. Bonnet, Brian K. Shoichet and 1 more. 2014

258 citations recorded by the source corpus.

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 β-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 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).

Subfields: Computational Theory and Mathematics, Molecular Biology, Organic Chemistry, Optimization & Training, Computational Chemistry & Drug Discovery

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In Computational Theory and Mathematics

In Molecular Biology

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Citations in the corpus

Molecular Docking and Structure-Based Drug Design Strategies (2015, background): “6 aimed to perform large-scale, covalent virtual screening [95].”
The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020, background): “Reactive cysteine residues on proteins have high nucleophilicity, which enables covalent binding with electrophilic small molecules [53, 54].”