The G protein-coupled receptors deorphanization landscape

Biochem Pharmacol. 2018 Jul:153:62-74. doi: 10.1016/j.bcp.2018.02.016. Epub 2018 Feb 15.


G protein-coupled receptors (GPCRs) are usually highlighted as being both the largest family of membrane proteins and the most productive source of drug targets. However, most of the GPCRs are understudied and hence cannot be used immediately for innovative therapeutic strategies. Besides, there are still around 100 orphan receptors, with no described endogenous ligand and no clearly defined function. The race to discover new ligands for these elusive receptors seems to be less intense than before. Here, we present an update of the various strategies employed to assign a function to these receptors and to discover new ligands. We focus on the recent advances in the identification of endogenous ligands with a detailed description of newly deorphanized receptors. Replication being a key parameter in these endeavors, we also discuss the latest controversies about problematic ligand-receptor pairings. In this context, we propose several recommendations in order to strengthen the reporting of new ligand-receptor pairs.

Keywords: Deorphanization; Drug target; G protein-coupled receptor; Orphan GPCR.

Publication types

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

MeSH terms

  • Animals
  • Humans
  • Ligands
  • Orphan Nuclear Receptors / immunology
  • Orphan Nuclear Receptors / metabolism*
  • Protein Binding / physiology
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / metabolism*


  • Ligands
  • Orphan Nuclear Receptors
  • Receptors, G-Protein-Coupled