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Cited by 1,667Computational Drug Discovery MethodsReceptor Mechanisms and SignalingProtein Interaction Studies and Fluorescence Analysis

Predicting new molecular targets for known drugs

Open access
Keiser, Michael J., Setola, Vincent, Irwin, John J., Laggner, Christian, Abbas, Atheir I., Hufeisen, Sandra J., Jensen, Niels H., Kuijer, Michael B. +9 more·2009·Nature
DOI 10.1038/nature08506PMC PMC2784146
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Abstract

Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H(4) receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.

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  • Psychotria viridis contains DMT, a hallucinogenic tryptamine that acts as a 5-HT1A/2A/2C agonist.

    “The latter plant contains DMT (9), a hallucinogenic tryptamine that acts as a 5-HT1A/2A/2C agonist [54,128].”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [128]

    In “New targets as primary sites of action” (page unavailable), the paper calls DMT a hallucinogen, reports binding to 5-HT1A, 5-HT2A and 5-HT2C, and demonstrates partial agonism at 5-HT2A. It does not establish 5-HT1A agonism or say that Psychotria viridis contains DMT; its reference list names an earlier study of 5-HT2C agonism. (LLM, conf=0.88)

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Cites

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Authors
Keiser, M. J., Setola, V., Irwin, J. J., Laggner, C., Abbas, A. I., Hufeisen, S. J., Jensen, N. H., Kuijer, M. B., Matos, R. C., Tran, T. B., Whaley, R., Glennon, R. A., Hert, J., Thomas, K. L. H., Edwards, D. D., Shoichet, B. K., & Roth, B. L.
Affiliations
  • University of California, San Francisco (US)
  • National Institute of Mental Health (US)
  • Case Western Reserve University (US)
  • University of North Carolina at Chapel Hill (US)
  • Virginia Commonwealth University (US)
  • Michigan Medicine (US)
Corresponding author
  • Shoichet, Brian K.
  • Roth, Bryan L.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2009-11
Volume
462
Issue
7270
Pages
175-181
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature08506
PMC
PMC2784146
OpenAlex
W2138512826
Cited by
1,667
References
4
Citations by year
2026: 50 · 2025: 56 · 2024: 75 · 2023: 80 · 2022: 85 · 2021: 93 · 2020: 115 · 2019: 114 · 2018: 99 · 2017: 79 · 2016: 109 · 2015: 117 · 2014: 109 · 2013: 132 · 2012: 134
FWCI
116.49
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UNC Libraries
Funders
  • National Science Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • European Bioinformatics Institute
  • Max Kade Foundation
  • European Commission
  • National Institutes of Health
  • National Institute of Mental Health (U19MH082441, R01MH061887)
  • National Institute on Drug Abuse (R01DA017204)
  • National Institute of General Medical Sciences (T32GM007250)
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 › Protein Interaction Studies and Fluorescence Analysis
Keywords
drug-target interactions, off-target effects, molecular similarity, adverse drug reactions, drug repurposing, protein targets, drug screening, serotonin transporter, histamine H4 receptor, N,N-dimethyltryptamine, serotonergic receptors, drug selectivity
MeSH terms
Animals, Drug Evaluation, Preclinical, Pharmaceutical Preparations, Humans, Ligands, Receptors, Serotonin, Substrate Specificity, United States, United States Food and Drug Administration, Databases, Factual, Mice, Knockout, Computational Biology, Mice, Off-Label Use, Drug-Related Side Effects and Adverse Reactions

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