SBIR-STTR Award

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, orexin, and chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. The overall goal of Phase I and II is to develop a focused library of 8,000 to 10,000 small molecules with a high probability of containing information rich ligands for any GPCR-PA+. The objective of Phase-I is to design and synthesize a 'test' library of 2,000 single, pure compounds and to validate the approach by screening it against at least two receptors. "Drug space" will be defined computationally by an analysis of the World Drug Index and a subspace.delineated using GPCR-PA+ ligands culled from the literature and Neurocrine's proprietary collection. A virtual library of >10[8] readily synthesizable, novel compounds will be enumerated and molecules selected for combinatorial synthesis that fall into the predicted subspace. Screening data will be compared to that obtained from a random matched collection. The completed library of approximately 10,000 molecules in Phase II will drive Neurocrine's drug discovery process against some of these receptors. PROPOSED COMMERCIAL APPLICATIONS:The project, if successful, will result in a library of small molecule compounds with a high probability of yielding multiple modestly 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

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. PROPOSED COMMERCIAL APPLICATIONS: 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.

Thesaurus Terms:
G protein, peptide chemical synthesis, peptide library, receptor coupling, receptor expression, technology /technique development computer system design /evaluation, hormone receptor, ligand, molecular biology information system, protein sequence high throughput technology