Chemical Diversity in the G Protein-Coupled Receptor Superfamily

Trends Pharmacol Sci. 2018 May;39(5):494-512. doi: 10.1016/ Epub 2018 Mar 22.


G protein-coupled receptors (GPCRs) are the largest family of cell signaling transmembrane proteins that can be modulated by a plethora of chemical compounds. Systematic cheminformatics analysis of structurally and pharmacologically characterized GPCR ligands shows that cocrystallized GPCR ligands cover a significant part of chemical ligand space, despite their limited number. Many GPCR ligands and substructures interact with multiple receptors, providing a basis for polypharmacological ligand design. Experimentally determined GPCR structures represent a variety of binding sites and receptor-ligand interactions that can be translated to chemically similar ligands for which structural data are lacking. This integration of structural, pharmacological, and chemical information on GPCR-ligand interactions enables the extension of the structural GPCR-ligand interactome and the structure-based design of novel modulators of GPCR function.

Keywords: G protein-coupled receptor (GPCR); structural cheminformatics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation
  • Chemistry, Pharmaceutical
  • Drug Design
  • Humans
  • Ligands
  • Polypharmacology
  • Receptors, G-Protein-Coupled / chemistry*
  • Structure-Activity Relationship


  • Ligands
  • Receptors, G-Protein-Coupled