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.
journal_name
Naturejournal_title
Natureauthors
Keiser MJ,Setola V,Irwin JJ,Laggner C,Abbas AI,Hufeisen SJ,Jensen NH,Kuijer MB,Matos RC,Tran TB,Whaley R,Glennon RA,Hert J,Thomas KL,Edwards DD,Shoichet BK,Roth BLdoi
10.1038/nature08506subject
Has Abstractpub_date
2009-11-12 00:00:00pages
175-81issue
7270eissn
0028-0836issn
1476-4687pii
nature08506journal_volume
462pub_type
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