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 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, California 94143-2550, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keiser
authors.forename: Vincent
authors.initials: V
authors.lastname: Setola
authors.forename: John J
authors.initials: JJ
authors.lastname: Irwin
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Atheir I
authors.initials: AI
authors.lastname: Abbas
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hufeisen
authors.forename: Niels H
authors.initials: NH
authors.lastname: Jensen
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kuijer
authors.forename: Roberto C
authors.initials: RC
authors.lastname: Matos
authors.forename: Thuy B
authors.initials: TB
authors.lastname: Tran
authors.forename: Ryan
authors.initials: R
authors.lastname: Whaley
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.forename: Jérôme
authors.initials: J
authors.lastname: Hert
authors.forename: Kelan L H
authors.initials: KL
authors.lastname: Thomas
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Edwards
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D000818:Animals; D019295:Computational Biology; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D056687:Off-Label Use; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D013379:Substrate Specificity; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011985:Receptors, Serotonin