Portal de Periódicos da CAPES

Discovery of Novel Chemotypes to a G-Protein-Coupled Receptor through Ligand-Steered Homology Modeling and Structure-Based Virtual Screening

2008; American Chemical Society; Volume: 51; Issue: 3 Linguagem: Inglês

10.1021/jm070759m

1520-4804

Claudio N. Cavasotto, Andrew Orry, Nicholas Murgolo, Michael Czarniecki, Sue Ann Kocsi, Brian E. Hawes, Kim A. O’Neill, Heather Hine, Marybeth S. Burton, Johannes Voigt, Ruben Abagyan, Marvin Bayne, Frederick J. Monsma,

Chemical Synthesis and Analysis

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.