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Identifying Targets for Drugs and Probes with Unknown Mechanisms of Action

Gregori-Puigjané, Elisabet, Setola, Vincent, Hert, Jérôme, Evans, Jon, Crews, Brenda C, Lounkine, Eugen, Marnett, Larry, Shoichet, Brian K and Roth, Bryan L (2012) Identifying Targets for Drugs and Probes with Unknown Mechanisms of Action. PNAS, 109 (28). pp. 11178-11183. ISSN 1091-6490


Notwithstanding their key roles in therapy and as probes for biology, as many as 7% of drugs have no known primary target, while up to 21% have been reported to lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “deorphanize” drugs that lack primary targets in DrugBank, MDDR and NPC databases. Surprisingly, for many of these drugs targets could be easily predicted. Too easily: whereas these targets were not previously known to us nor to the common databases, almost all could be readily confirmed by literature search, leaving only 13 FDA drugs with unknown targets; this suggests that the number of drugs without molecular targets is far fewer than reported. For worldwide drugs in MDDR, the number of molecules without sensible targets similarly dropped; from 352 to 44 (4%), and to 3% in the NPC. Nevertheless, there remained at least seven drugs for which targets appeared to be genuinely unknown and for which sensible mechanism of action targets could be predicted. These included the anti-cough drugs clemastine, cloperastine and nepinalone, the anti-emetic benzquinamide, the muscle relaxant cyclobenzaprine, the analgesic nefopam and the immunomodulator lobenzarit. For each of these, the predicted targets were confirmed experimentally with affinities ranging from 20 nM to mid-micromolar, all within the physiological concentration ranges achieved by the drugs. This approach to target association may be turned toward identifying established molecules as chemical probes for biology. A combination of chemoinformatic and literature-based specificity found over 100 drugs that can be used as chemical probes by standard definitions, and over 50 by stringent criteria.

Item Type: Article
Additional Information: The NIBR contribution to this project constituted the initial finding that Benzquinamide did not bind its proposed primary targets, and in assessment of drug selectivity for their use as tool compounds.
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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