Identifying mechanism-of-action targets for drugs and probes.
Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest.
Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, San Francisco, CA 94143-2550, USA.
Elisabet
E
Gregori-Puigjané
Vincent
V
Setola
Jérôme
J
Hert
Brenda A
BA
Crews
John J
JJ
Irwin
Eugen
E
Lounkine
Lawrence
L
Marnett
Bryan L
BL
Roth
Brian K
BK
Shoichet
D019295:Computational Biology / Q000379:methods*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D016503:Drug Delivery Systems; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015335:Molecular Probes / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry; D012984:Software; D013678:Technology, Pharmaceutical / Q000379:methods*; D014481:United States; D014486:United States Food and Drug Administration; D062367:ortho-Aminobenzoates / Q000737:chemistry
D008024:Ligands; D015335:Molecular Probes; D004364:Pharmaceutical Preparations; D062367:ortho-Aminobenzoates; C015735:lobenzarit