Emerging Approaches to GPCR Ligand Screening for Drug Discovery

The superfamily of G-protein-coupled receptors (GPCRs) represents the largest class of cell surface receptors and, thus, a prominent family of drug targets. Recently, there has been significant progress in determination of GPCR crystal structures. The structure-based ligand discovery of GPCRs is emerging as a powerful path to drug development. Sensor surface-immobilized GPCRs can identify direct receptor–ligand interactions of a range of chemical libraries. This type of screening shows great promise as an alternative strategy for ligand discovery. Here, we summarize the most recent developments of structure- and sensor-based GPCR ligand discovery. We also highlight certain areas where GPCRs harbor great potential for the development of novel therapeutics, emphasizing the strategic approaches that may yield significant breakthroughs.

TrendsG-Protein-coupled receptors (GPCRs) are the largest class of cell surface receptors and, thus, represent targets for approximately one-third of currently marketed drugs.The emergence of GPCR crystal structures has allowed the virtual screening and identification of novel antagonist and agonist ligands with reasonable affinity and selectivity.The sensor-based screening approach is emerging as a powerful strategy to uncover novel GPCR ligands.The sensor-based approach harbors a unique potential for the identification of allosteric ligands and the screening of GPCR–ligand signaling complexes.Recent advances in the area of GPCR biology open up new frontiers in GPCR targeting, such as biased ligands, allosteric ligands, and intracellular modulators.