Bridging the gap: bitopic ligands of G-protein-coupled receptors

Although classical approaches to G-protein-coupled receptor (GPCR) drug design have targeted the orthosteric binding site, potentially all GPCRs possess druggable allosteric sites. In addition, it is clear that GPCRs can adopt multiple active states linked to distinct functional outcomes that can be stabilized by both allosteric and orthosteric ligands. Recent studies have begun to explore the possibilities of linking orthosteric and allosteric pharmacophores to yield 'bitopic' ligands as an approach to achieve improved receptor affinity or selectivity. Furthermore, it is possible that previously identified functionally selective drugs may represent unappreciated bitopic ligands at this important class of drug targets. Here we discuss both the potential of bitopic ligands in GPCR drug discovery and the challenges associated with the design of such ligands.