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Strategies to Discover Unexpected Targets for Drugs Active at G Protein–Coupled Receptors

Allen, John A., Roth, Bryan L.·2011·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-010510-100553

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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.

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Authors: Allen, J. A., & Roth, B. L.
Affiliations: University of North Carolina at Chapel Hill (US)
ORCID: Allen, John A.
Roth, Bryan L.
Venue: Annual Review of Pharmacology and Toxicology
Publisher: Annual Reviews
Published: 2011-02-10
Volume: 51
Issue: 1
Pages: 117-144
ISSN: 0362-1642 (ISSN-L)
1545-4304
DOI: 10.1146/annurev-pharmtox-010510-100553
OpenAlex: W2160203886
Cited by: 216
References: 145
Citations by year: 2026: 3 · 2025: 6 · 2024: 16 · 2023: 12 · 2022: 15 · 2021: 7 · 2020: 10 · 2019: 15 · 2018: 15 · 2017: 14 · 2016: 10 · 2015: 22 · 2014: 21 · 2013: 22 · 2012: 17
FWCI: 1.96
Type: journal article
Language: en
Open access: closed
Locations: The Annual Review of Pharmacology and Toxicology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
U.S. Public Health Service (HHSN-271-2008-00025-C)
National Institute of Mental Health (U19MH082441, R01MH061887)
National Institute on Drug Abuse (R01DA017204)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD040127)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: G protein-coupled receptors, polypharmacology, cheminformatics, adverse drug reactions, receptor selectivity, mechanisms of drug action, drug development
MeSH terms: Animals, Pharmaceutical Preparations, Humans, Ligands, Drug Design, Drug Delivery Systems, Computational Biology, Receptors, G-Protein-Coupled, Drug Discovery, Drug-Related Side Effects and Adverse Reactions

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Strategies to Discover Unexpected Targets for Drugs Active at G Protein–Coupled Receptors

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