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

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• 作者：Claudio N. Cavasotto ; Andrew J. W. Orry ; Nicholas J. Murgolo ; Michael F. Czarniecki ; Sue Ann Kocsi ; Brian E. Hawes ; Kim A. O’ ; Neill ; Heather Hine ; Marybeth S. Burton ; Johannes H. Voigt ; Ruben A.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：581 - 588
• 全文大小：904K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

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.