Relating protein pharmacology by ligand chemistry
Open accessAbstract
The identification of protein function based on biological information is an area of intense research. Here we consider a complementary technique that quantitatively groups and relates proteins based on the chemical similarity of their ligands. We began with 65,000 ligands annotated into sets for hundreds of drug targets. The similarity score between each set was calculated using ligand topology. A statistical model was developed to rank the significance of the resulting similarity scores, which are expressed as a minimum spanning tree to map the sets together. Although these maps are connected solely by chemical similarity, biologically sensible clusters nevertheless emerged. Links among unexpected targets also emerged, among them that methadone, emetine and loperamide (Imodium) may antagonize muscarinic M3, alpha2 adrenergic and neurokinin NK2 receptors, respectively. These predictions were subsequently confirmed experimentally. Relating receptors by ligand chemistry organizes biology to reveal unexpected relationships that may be assayed using the ligands themselves.
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- Authors
- Keiser, M. J., Roth, B. L., Armbruster, B. N., Ernsberger, P., Irwin, J. J., & Shoichet, B. K.
- Affiliations
- University of California, San Francisco (US)
- University of North Carolina at Chapel Hill (US)
- National Institute of Mental Health (US)
- Corresponding author
- Irwin, John J
- Shoichet, Brian K
- Venue
- Nature Biotechnology
- Published
- 2007-02
- Volume
- 25
- Issue
- 2
- Pages
- 197-206
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2162011385
- Cited by
- 2,402
- References
- 48
- Citations by year
- 2026: 243 · 2025: 223 · 2024: 215 · 2023: 206 · 2022: 176 · 2021: 180 · 2020: 149 · 2019: 128 · 2018: 109 · 2017: 85 · 2016: 94 · 2015: 95 · 2014: 78 · 2013: 105 · 2012: 77
- FWCI
- 64.47
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Johns Hopkins University
- National Institute of General Medical Sciences (GM71896, F32GM074554, T32GM067547, GM67547, R01GM071896)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- ligand topology, drug-target interactions, protein clustering, minimum spanning tree, M3 muscarinic receptor, alpha2-adrenoceptors, methadone, emetine, loperamide
- MeSH terms
- Binding Sites, Pharmaceutical Preparations, Ligands, Protein Binding, Proteins, Drug Design, Sequence Alignment, Drug Delivery Systems, Sequence Analysis, Protein, Protein Interaction Mapping, Databases, Protein
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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