Novel Chemotypes to Melanin-Concentrating Hormone Receptor 1 Discovered Through Ligand-Steered Homology Modeling and Virtual Screening

CAVASOTTO, CLAUDIO N.

San Diego, CA

Conferencia; Drug Discovery Chemistry; 2008

Melanin-concentrating hormonereceptor 1 belongs to the class A of G-protein-coupled receptors.  It is involved in feeding and energy balance,and thus constitutes an attractive target for antiobesity therapy.  However, the discovery of novel antagonistchemotypes through structure-based virtual screening is hampered by the lack ofan available experimental structure. A ligand-steered homology modelingmethod was developed, where the information about existing antagonists isincorporated directly into the modeling of the binding pocket.  The models thus generated were used invirtual screening of circa 200,000 compounds. Of the 129 top-scoring compounds, six were found to be active in thelow-micromolar range.  This performancewas found to be 10-fold better than high throughput screening.