New paradigms in GPCR drug discovery

Biochem Pharmacol. 2015 Dec 15;98(4):541-55. doi: 10.1016/j.bcp.2015.08.085. Epub 2015 Aug 8.


G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The identification of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient's genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help reverse the current narrowing of the pharmaceutical pipeline.

Keywords: Drug discovery; GPCR; Inhibitors; Signaling; X-ray crystallography; structure-based design.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Design
  • Drug Discovery / methods
  • Drug Discovery / trends*
  • Humans
  • Protein Structure, Secondary
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / physiology


  • Receptors, G-Protein-Coupled