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.
The project, if successful, will result in a library of small molecule compounds with a high probability of yielding multiple modesty, active molecules for any G-protein coupled receptor for positively charged peptide ligands. From this information, an interactive process of design, synthesis and screening will afford potent, selective ligands, Thus, this library will accelerate Neurocrine's in-house drug discovery efforts focused on members of this class of receptors and against novel members as they become available. Additionally, the library may be licensed to other companies.
| Lavrador, Karine; Murphy, Brian; Saunders, John et al. (2004) A screening library for peptide activated G-protein coupled receptors. 1. The test set. J Med Chem 47:6864-74 |
