Predicting new molecular targets for known drugs.
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.
Keiser
Michael J
MJ
Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, California 94143-2550, USA.
Setola
Vincent
V
Irwin
John J
JJ
Laggner
Christian
C
Abbas
Atheir I
AI
Hufeisen
Sandra J
SJ
Jensen
Niels H
NH
Kuijer
Michael B
MB
Matos
Roberto C
RC
Tran
Thuy B
TB
Whaley
Ryan
R
Glennon
Richard A
RA
Hert
Jérôme
J
Thomas
Kelan L H
KL
Edwards
Douglas D
DD
Shoichet
Brian K
BK
Roth
Bryan L
BL
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
D008024:Ligands; D004364:Pharmaceutical Preparations; D011985:Receptors, Serotonin