RT Journal Article SR Electronic T1 How Physiologic Targets Can Be Distinguished from Drug-Binding Proteins JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1 OP 6 DO 10.1124/molpharm.120.000186 VO 100 IS 1 A1 Kojo Mensa-Wilmot YR 2021 UL http://molpharm.aspetjournals.org/content/100/1/1.abstract AB In clinical trials, some drugs owe their effectiveness to off-target activity. This and other observations raise a possibility that many studies identifying targets of drugs are incomplete. If off-target proteins are pharmacologically important, it will be worthwhile to identify them early in the development process to gain a better understanding of the molecular basis of drug action. Herein, we outline a multidisciplinary strategy for systematic identification of physiologic targets of drugs in cells. A drug-binding protein whose genetic disruption yields very similar molecular effects as treatment of cells with the drug may be defined as a physiologic target of the drug. For a drug developed with a rational approach, it is desirable to verify experimentally that a protein used for hit optimization in vitro remains the sole polypeptide recognized by the drug in a cell.SIGNIFICANCE STATEMENT A body of evidence indicates that inactivation of many drug-binding proteins may not cause the pharmacological effects triggered by the drugs. A multidisciplinary cell-based approach can be of great value in identifying the physiologic targets of drugs, including those developed with target-based strategies.