Ligand-specific pharmacogenetic effects of nonsynonymous mutations

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 ...

Source: Pharmacogenetics and Genomics - May 1, 2021 Category: Genetics & Stem Cells Tags: Mini Review Source Type: research