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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\u2014approved 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.<\/jats:p>","DOI":"10.1073\/pnas.1204524109","type":"journal-article","created":{"date-parts":[[2012,6,18]],"date-time":"2012-06-18T23:15:14Z","timestamp":1340061314000},"page":"11178-11183","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":175,"title":["Identifying mechanism-of-action targets for drugs and probes"],"prefix":"10.1073","volume":"109","author":[{"given":"Elisabet","family":"Gregori-Puigjan\u00e9","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, San Francisco, CA 94143-2550;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Setola","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, 4009 Genetics Medicine CB7365, Chapel Hill, NC 27599-7365;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Hert","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, San Francisco, CA 94143-2550;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda A.","family":"Crews","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, 23rd Avenue South and Pierce Room 850 RRB, Nashville, TN 37232-0146; 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