Research Project
6143986
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.
