Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 51, 2011
Volume 51, Issue -, Pages 117-144Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010510-100553
Keywords
high-throughput screening; polypharmacology; receptorome; valvulopathy; drug side effects; similarity ensemble approach
Categories
Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [T32HD040127] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [U19MH082441, R01MH061887] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA027170, R01DA017204] Funding Source: NIH RePORTER
- NICHD NIH HHS [T32HD040127-07] Funding Source: Medline
- NIDA NIH HHS [R01 DA017204, R01 DA027170, R01DA017204] Funding Source: Medline
- NIMH NIH HHS [U19MH82441, U19 MH082441, R01 MH061887, R01MH61887] Funding Source: Medline
- PHS HHS [HHSN-271-2008-00025-C] Funding Source: Medline
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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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