J Med Chem. 2008 Feb 14;51(3):581-8. Epub 2008 Jan 17.

Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening.

Cavasotto CN, Orry AJ, Murgolo NJ, Czarniecki MF, Kocsi SA, Hawes BE, O'Neill KA, Hine H, Burton MS, Voigt JH, Abagyan RA, Bayne ML, Monsma FJ Jr.

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MolSoft LLC, La Jolla, CA 92037, USA. Claudio.N.Cavasotto@uth.tmc.edu

Abstract

Melanin-concentrating hormone receptor 1 (MCH-R1) is a G-protein-coupled receptor (GPCR) and a target for the development of therapeutics for obesity. The structure-based development of MCH-R1 and other GPCR antagonists is hampered by the lack of an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands is used explicitly to shape and optimize the binding site) followed by docking-based virtual screening. Top scoring compounds identified virtually were tested experimentally in an MCH-R1 competitive binding assay, and six novel chemotypes as low micromolar affinity antagonist "hits" were identified. This success rate is more than a 10-fold improvement over random high-throughput screening, which supports our ligand-steered method. Clearly, the ligand-steered homology modeling method reduces the uncertainty of structure modeling for difficult targets like GPCRs.

PMID:: 18198821; [PubMed - indexed for MEDLINE]

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