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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 β1 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 H4 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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Acknowledgements

Supported by grants from the National Institutes of Health (NIH) supporting chemoinformatics (to B.K.S. and J.J.I.) and NIH grants and contracts supporting drug discovery and receptor pharmacology (to B.L.R). M.J.K., J.H. and C.L. were supported by fellowships from the National Science Foundation, the 6th FP of the European Commission, and the Max Kade Foundation, respectively. B.L.R. was also supported by a Distinguished Investigator Award from the NARSAD and the Michael Hooker Chair. We thank T. Oprea of Sunset Molecular for WOMBAT, Elsevier MDL for the MDDR, Scitegic for PipelinePilot, J. Overington of the European Bioinformatics Institute (EMBL-EBI) for StARlite, Daylight Chemical Information Systems Inc. for the Daylight toolkit, and J. Gingrich for 5-HT2A knockout mice.

Author Contributions B.K.S., J.J.I. and M.J.K. developed the ideas for SEA. M.J.K. wrote the SEA algorithms, undertook the calculations, and identified the off-targets reported here, typically vetted with J.J.I. and B.K.S., unless otherwise noted below. M.J.K. wrote the naive Bayesian classifier algorithms with assistance from J.H. With assistance from B.K.S. and J.J.I., C.L. identified off-targets for Fabahistin, K.L.H.T. identified off-targets for Prozac and Paxil, and D.D.E. identified the off-target for Rescriptor. V.S. and B.L.R. designed empirical tests of the predictions, analysed and interpreted data, and performed experiments. V.S., T.B.T., R.W., R.C.M., A.A., N.H.J. and M.B.K. performed empirical testing of the predictions. V.S., S.J.H. and R.A.G. generated materials for the experiments. M.J.K., B.K.S. and B.L.R. wrote the manuscript with contributions and review from V.S. All authors discussed the results and commented on the manuscript.

Author information

Author notes

    • Michael J. Keiser
    •  & Vincent Setola

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmaceutical Chemistry,

    • Michael J. Keiser
    • , John J. Irwin
    • , Christian Laggner
    • , Jérôme Hert
    • , Kelan L. H. Thomas
    • , Douglas D. Edwards
    •  & Brian K. Shoichet
  2. Graduate Group in Bioinformatics, University of California San Francisco, 1700 4th Street, San Francisco, California 94143-2550, USA

    • Michael J. Keiser
  3. NIMH Psychoactive Drug Screening Program, Department of Pharmacology,

    • Vincent Setola
    • , Michael B. Kuijer
    • , Roberto C. Matos
    • , Thuy B. Tran
    • , Ryan Whaley
    •  & Bryan L. Roth
  4. Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA

    • Atheir I. Abbas
  5. Department of Pharmacology and Division of Medicinal Chemistry and Natural Products, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina 27759, USA

    • Sandra J. Hufeisen
    • , Niels H. Jensen
    •  & Bryan L. Roth
  6. Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, 410 North 12th Street, PO Box 980540, Richmond, Virginia 23298-0540, USA

    • Richard A. Glennon
  7. University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA

    • Kelan L. H. Thomas

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Competing interests

B.K.S., M.J.K. and J.J.I. are founders of SeaChange Pharmaceuticals, Inc., a company that uses SEA technology.

Corresponding authors

Correspondence to Brian K. Shoichet or Bryan L. Roth.

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    This file contains Supplementary Tables 1-3 and Supplementary Figures 1-10 with Legends.

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https://doi.org/10.1038/nature08506

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