Maximizing serendipity: strategies for identifying ligands for orphan G-protein-coupled receptors

G-protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors within the human genome, and historically these have been a rich source of targets for small-molecule modulation and therapeutic intervention. As a result of genome closure, numerous novel GPCRs that have unknown ligands and function were identified, and termed 'orphans'. These are considered potential new targets for drug discovery, and many companies have been focusing on ligand identification using high-throughput functional assays in the quest to discover a tool to further probe the pathophysiolgical role of these new receptors. In the past five years, approximately 50 receptors have been ligand-paired, although putative functions have only been described for the minority. The number of new small-molecule modulators that ultimately make it to the market will measure the success of this initiative.