GPCR drug discovery through the exploitation of allosteric drug binding sites

Recept Channels. 2002;8(5-6):261-8.


G-protein-coupled receptors (GPCRs) represent the most important class of drug targets both in terms of therapeutic benefit and pharmaceutical sales. The majority of current GPCR drugs have been identified in ligand binding assays and interact with the receptor in a competitive manner with the natural ligand. There is increasing evidence that it is possible to identify GPCR agonist and antagonist ligands that do not interact at the natural ligand binding site, rather such compounds interact elsewhere on the receptor to modulate receptor activity. This finding allows the possibility that there may be many as yet uncharacterized drug binding sites within the GPCR that could be exploited for therapeutic intervention. The characterization of such "allosteric" ligand interaction sites, following the identification of molecules capable of interacting at these sites, would be expected to lead to the identification of drug molecules with improved selectivity and efficacy. Such activities may enable the identification of selective ligands at GPCRs for which competitive natural ligand binding screens have been unsuccessful. In this manuscript we review known examples of GPCR allosteric ligands, the functional assay technologies that are being employed to identify further ligands of this type, and the potential benefit that may result from the identification of such ligands.

Publication types

  • Review

MeSH terms

  • Allosteric Site
  • Binding Sites
  • Biochemistry / methods*
  • Dose-Response Relationship, Drug
  • Drug Design
  • GTP-Binding Proteins / chemistry*
  • GTP-Binding Proteins / metabolism*
  • Inhibitory Concentration 50
  • Ions*
  • Ligands
  • Protein Binding
  • Receptors, Cell Surface / chemistry*


  • Ions
  • Ligands
  • Receptors, Cell Surface
  • GTP-Binding Proteins