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

被引：134

作者：

Cavasotto, Claudio N. ^{[1
]}

Orry, Andrew J. W. ^{[1
]}

Murgolo, Nicholas J. ^{[2
]}

Czarniecki, Michael F. ^{[3
]}

Kocsi, Sue Ann ^{[3
]}

Hawes, Brian E. ^{[4
]}

O'Neill, Kim A. ^{[4
]}

Hine, Heather ^{[3
]}

Burton, Marybeth S. ^{[3
]}

Voigt, Johannes H. ^{[5
]}

Abagyan, Ruben A. ^{[7
]}

Bayne, Marvin L. ^{[2
]}

Monsma, Frederick J., Jr. ^{[6
]}

机构：

[1] MolSoft LLC, La Jolla, CA 92037 USA

[2] Schering Plough Res Inst, Dept Discovery Technol, Kenilworth, NJ 07033 USA

[3] Schering Plough Res Inst, Dept Chem Technol, Kenilworth, NJ 07033 USA

[4] Schering Plough Res Inst, Dept Cardiovasc Biol, Kenilworth, NJ 07033 USA

[5] Schering Plough Res Inst, Dept Struct Chem, Kenilworth, NJ 07033 USA

[6] Schering Plough Res Inst, Dept New Lead Discovery, Kenilworth, NJ 07033 USA

[7] Scripps Res Inst, La Jolla, CA 92037 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 03期

关键词：

D O I：

10.1021/jm070759m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：581 / 588

页数：8

共 69 条

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