Predicting new molecular targets for known drugs

Whereas drugs are intended to be selective, at least some bind to several physiologic targets, explaining both side effects and efficacy. As many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here, we compared 3,665 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-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 such, the drug DMT on serotonergic receptors, was confirmed in a knock-out mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.