Mini ReviewLigand-specific pharmacogenetic effects of nonsynonymous mutationsMorningstar-Kywi, Noama; Haworth, Ian S.a; Mosley, Scott A.bAuthor Information aDepartments of Pharmacology and Pharmaceutical Sciences bDepartments of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA Received 18 September 2020 Accepted 12 November 2020 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.pharmacogeneticsandgenomics.com. Correspondence to Scott A. Mosley, PharmD, Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC B15C, Los Angeles, California 90089, USA, Tel: +(323) 442 0355; e-mail: [email protected] Pharmacogenetics and Genomics: June 2021 - Volume 31 - Issue 4 - p 75-82 doi: 10.1097/FPC.0000000000000424 Buy SDC Metrics Abstract In pharmacogenomics, variable receptor phenotypes, resulting from genetic polymorphisms, are often described as a change in protein function or regulation observed upon exposure to a drug. However, in some instances, phenotypes are defined using a class of medications rather than individual drugs. This paradigm assumes that a variation associated with a drug response phenotype will retain the magnitude and direction of the effect for other drugs with the same mechanism of action. However, nonsynonymous polymorphisms may have ligand-specific effects. The purpose of this study was to investigate the potential for point mutations to asymmetrically affect the binding of different drugs to a common target. Ligand binding data from site-directed mutagenesis studies on five G-protein coupled receptors (beta-1 and -2 adrenergic, dopamine D2, angiotensin II and mu-opioid receptor) were collected and analyzed. Binding data from 81 studies for 253 ligands with 447 mutant proteins, including 10 naturally occurring human variants, were analyzed, yielding 1989 mutation–ligand pairs. Fold change in binding affinity for mutant proteins, relative to the wild-type, for different drugs was examined for ligand-specific effects, with a fold-change difference of one or more orders of magnitude between agents considered significant. Of the mutations examined, 49% were associated with ligand-specific effects. One human variant (T164I, beta-2 adrenergic receptor) showed ligand-specific effects for antiasthmatic agents. These results indicate that ligand-specific changes in binding are a possible consequence of missense mutations. This implies that caution needs to be exercised when grouping drugs together during design or interpretation of genotype–phenotype association studies. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.