Predicting new molecular targets for known drugs

Michael J. Keiser, Vincent Setola, John J. Irwin, Christian Laggner, Atheir I. Abbas, Sandra J. Hufeisen, Niels H. Jensen, Michael B. Kuijer, Roberto C. Matos, Thuy B. Tran, Ryan Whaley, Richard A. Glennon, Jérme Hert, Kelan L.H. Thomas, Douglas D. Edwards, Brian K. Shoichet, Bryan L. Roth

Research output: Contribution to journalArticlepeer-review

1294 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)175-181
Number of pages7
Issue number7270
StatePublished - Nov 12 2009
Externally publishedYes

ASJC Scopus subject areas

  • General


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