@article{b66b227601e94c6c9233f09b0a7d5de3,
title = "Predicting new molecular targets for known drugs",
abstract = "Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drugĝ€{"}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 Β 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 drugĝ€{"}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.",
author = "Keiser, {Michael J.} and Vincent Setola and Irwin, {John J.} and Christian Laggner and Abbas, {Atheir I.} and Hufeisen, {Sandra J.} and Jensen, {Niels H.} and Kuijer, {Michael B.} and Matos, {Roberto C.} and Tran, {Thuy B.} and Ryan Whaley and Glennon, {Richard A.} and J{\'e}rme Hert and Thomas, {Kelan L.H.} and Edwards, {Douglas D.} and Shoichet, {Brian K.} and Roth, {Bryan L.}",
note = "Funding Information: 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. Copyright: Copyright 2011 Elsevier B.V., All rights reserved.",
year = "2009",
month = nov,
day = "12",
doi = "10.1038/nature08506",
language = "English (US)",
volume = "462",
pages = "175--181",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7270",
}