A perspective on more effective GPCR-targeted drug discovery efforts

Background: G-protein-coupled receptors (GPCRs) form the largest receptor family in mammalian genomes and over the years they have repeatedly proven themselves to be druggable targets. The activation of a GPCR (usually by ligand binding) results in conformational changes that lead to G-protein coupling with subsequent activation of downstream effectors and ultimately a cellular response. GPCRs can be modulated at several strategic signaling positions including ligand binding, G-protein coupling, phosphorylation, internalization, and recycling. Objective: As the complexities of GPCR activation and signaling become more recognized, new technologies have been sought for the identification of ligands that can alter not only receptor activation but also receptor action. Methods: Taking into consideration the key contact sites, this review will cover several points to bear in mind both when developing a screening campaign for a GPCR and when validating the hits obtained from those primary screens. Results/conclusions: The final selection of which screen to use for a given GPCR should take into account the end goal of the drug, such as inflammation, and work towards utilizing screens that allow physiological end points in this case chemotaxis, relevant cell types, and endogenous receptors whenever possible.