The G protein-coupled receptors deorphanization landscape

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• G protein-coupled receptors (GPCRs) represent the largest membrane protein family and a primary source for drug discovery.
• Many GPCRs remain understudied, hindering the development of novel therapeutics, with approximately 100 orphan receptors lacking identified ligands and functions.
• The pursuit of novel ligands for these elusive receptors has seen diminished intensity.

Purpose of the Study:

• To provide an updated overview of strategies for assigning functions to understudied GPCRs.
• To highlight recent advancements in identifying endogenous ligands for GPCRs, including newly deorphanized receptors.
• To address controversies surrounding ligand-receptor pairings and propose recommendations for robust reporting.

Main Methods:

• Review and synthesis of recent literature on GPCR ligand discovery and functional assignment.
• Analysis of newly identified endogenous ligands and deorphanized receptors.
• Discussion of challenges and controversies in ligand-receptor validation.

Main Results:

• Several strategies are being employed to uncover the functions of understudied and orphan GPCRs.
• Recent progress has led to the deorphanization of several GPCRs, expanding the repertoire of known ligand-receptor interactions.
• Replication issues and problematic ligand-receptor pairings present significant challenges in the field.

Conclusions:

• Continued research into GPCRs is essential for advancing therapeutic strategies.
• Standardized reporting and rigorous validation are critical for reliable ligand-receptor pair identification.
• Addressing controversies and improving reproducibility will accelerate the discovery of novel GPCR-targeted drugs.