Covalent docking of large libraries for the discovery of chemical probes
Open accessAbstract
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 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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Covalent inhibitors achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein.
“Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [54]
Reactive cysteine residues on proteins have high nucleophilicity, which enables covalent binding with electrophilic small molecules.
“Reactive cysteine residues on proteins have high nucleophilicity, which enables covalent binding with electrophilic small molecules [53, 54].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [54]
DOCKovalent uses non-covalent docking methods to pre-generate conformations and states for an electrophilic virtual library and then samples each state against the target nucleophile.
“DOCKovalent uses non-covalent docking methods to pre-generate conformations and states for an electrophilic virtual library and then samples each state against the target nucleophile.”
From Advances in covalent drug discovery (2022) · cites this paper as [169]
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- Authors
- London, N., Miller, R. M., Krishnan, S., Uchida, K., Irwin, J. J., Eidam, O., Gibold, L., Cimermančič, P., Bonnet, R., Shoichet, B. K., & Taunton, J.
- Affiliations
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Ontario Institute for Cancer Research (CA)
- Inserm (FR)
- Corresponding author
- Shoichet, Brian K
- Taunton, Jack
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2014-10-26
- Volume
- 10
- Issue
- 12
- Pages
- 1066-1072
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4232467
- OpenAlex
- W2002368219
- Cited by
- 274
- References
- 60
- Citations by year
- 2026: 23 · 2025: 16 · 2024: 19 · 2023: 27 · 2022: 25 · 2021: 24 · 2020: 28 · 2019: 29 · 2018: 20 · 2017: 16 · 2016: 29 · 2015: 14 · 2014: 4
- FWCI
- 23.39
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-02-17)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (NIH GM71896, T32GM064337, T32GM067547, GM59957, R01GM059957, R01GM071896)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- chemical probes, reversible covalent inhibitors, AmpC beta-lactamase, catalytic serine, cysteine, covalent docking, ligand efficiency, web server
- MeSH terms
- Animals, Bacterial Proteins, beta-Lactamases, Cysteine, Gram-Negative Bacteria, Humans, Ligands, Protein Binding, Recombinant Proteins, Serine, Molecular Probes, COS Cells, Ribosomal Protein S6 Kinases, 90-kDa, Protein Kinase Inhibitors, Janus Kinase 3, Small Molecule Libraries, Drug Discovery, Hydrophobic and Hydrophilic Interactions, Molecular Docking Simulation, beta-Lactamase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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