Strategies to discover unexpected targets for drugs active at G protein-coupled receptors

John A. Allen, Bryan L. Roth

Research output: Contribution to journalArticlepeer-review

141 Scopus citations


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 offtargets 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.

Original languageEnglish (US)
Pages (from-to)117-144
Number of pages28
JournalAnnual review of pharmacology and toxicology
StatePublished - Feb 10 2011
Externally publishedYes


  • drug side effects
  • high-throughput screening
  • polypharmacology
  • receptorome
  • similarity ensemble approach
  • valvulopathy

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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