A SCREENING LIBRARY FOR PEPTIDE-ACTIVATED GPCR'S

One subset of the G-protein coupled receptor (GPCR) superfamily is that which is activated by a peptide carrying an obligatory positively charged residue (GPCR-PA+). This subclass is exemplified by receptors for melanocortins, GnRH galanin, MCH, orexin and chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. In Phase-I, a region of chemical property space enriched in GPCR ligands was identified. This was used to design and synthesize a 'test' library of 2025 single, pure compounds to sample portions of this property space associated with GPCR-PA+ ligands. This library was evaluated by high-throughput screening against three different receptors and found to be highly enriched in ligands (4.5 to 61-fold) compared to a control set of 2024 randomly selected compounds. In Phase II we propose to expand the size of this library to at least 6749 compounds to complete the sampling of this GPCR-PA+ ligand-rich region and to better define it's borders. This completed library will be screened against an expanded array of receptor targets and hits so identified used as a starting point for lead optimization against a selected target. The resulting library should be a valuable resource for the rapid identification of ligands to a range of therapeutically important receptors.