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

CAVASOTTO, CLAUDIO N.; ORRY, ANDREW J.; MURGOLO, NICHOLAS J.; CZARNIECKI, M.F.; KOCS, S.A.; HAWES, B.E.; O'NEILL, K.A.; HINE, H.; BURTON, M.S.; VOIGT, JOHANN H.; BAYNE, M.L.; MONSMA, FREDERIC J.

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Año: 2008 vol. 51 p. 581 - 588

0022-2623

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.