Strategies to Discover Unexpected Targets for Drugs Active at G Protein–Coupled Receptors
- 10 February 2011
- journal article
- review article
- Published by Annual Reviews in Annual Review of Pharmacology and Toxicology
- Vol. 51 (1), 117-144
- https://doi.org/10.1146/annurev-pharmtox-010510-100553
Abstract
G protein–coupled receptors (GPCRs) are an evolutionarily conserved family of signaling molecules comprising approximately 2% of the human genome; this receptor family remains a central focus in basic pharmacology studies and drug discovery efforts. Detailed studies of drug action at GPCRs over the past decade have revealed existing and novel ligands that exhibit polypharmacology—that is, drugs with activity at more than one receptor target for which they were designed. These “off-target” drug actions can be a liability that causes adverse side effects; however, in several cases, drugs with less selectivity demonstrate better clinical efficacy. Here we review physical screening and cheminformatic approaches that define drug activity at the GPCR receptorome. In many cases, such profiling has revealed unexpected targets that explain therapeutic actions as well as off-targets underlying drug side effects. Such drug-receptor profiling has also provided new insights into mechanisms of action of existing drugs and has suggested directions for future drug development.Keywords
This publication has 101 references indexed in Scilit:
- Prediction and Evaluation of Protein Farnesyltransferase Inhibition by Commercial DrugsJournal of Medicinal Chemistry, 2010
- p90 Ribosomal S6 Kinase 2, a Novel GPCR Kinase, Is Required for Growth Factor-Mediated Attenuation of GPCR SignalingBiochemistry, 2010
- Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic PropertiesNeuropsychopharmacology, 2009
- Predicting new molecular targets for known drugsNature, 2009
- Structure-Based Design, Synthesis, and Biochemical and Pharmacological Characterization of Novel Salvinorin A Analogues as Active State Probes of the κ-Opioid ReceptorBiochemistry, 2009
- Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disordersTrends in Pharmacological Sciences, 2009
- Insights into the regulation of 5-HT2A serotonin receptors by scaffolding proteins and kinasesNeuropharmacology, 2008
- Anatomical Profiling of G Protein-Coupled Receptor ExpressionCell, 2008
- Quantifying the Relationships among Drug ClassesJournal of Chemical Information and Modeling, 2008
- Orphan GPCR researchBritish Journal of Pharmacology, 2008