RT Journal Article
SR Electronic
T1 How Physiological Targets Can Be Distinguished from Drug-binding Proteins
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP MOLPHARM-EMC-2020-000186
DO 10.1124/molpharm.120.000186
A1 Kojo Mensa-Wilmot
YR 2021
UL http://molpharm.aspetjournals.org/content/early/2021/05/03/molpharm.120.000186.abstract
AB Some drugs in clinical trial owe their effectiveness to "off-target" activity. This and other observations raise a possibility that many studies to identify targets of drugs are incomplete. If "off-target" proteins are pharmacologically important it will be worthwhile to identify them early in the development process, for a better understanding of the molecular basis of drug action. Herein, we outline a multidisciplinary strategy for systematic identification of physiological 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 physiological 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 Many drug-binding proteins may not be the physiological targets whose inhibition compromises cell function of viability. A systematic approach involving several molecular disciplines is offered to help investigators to distinguish between binding proteins and the biological targets of drugs.