Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening

被引：124

作者：

Tikhonova, Irina G. ^{[1
]}

Sum, Chi Shing ^{[2
]}

Neumann, Susanne ^{[2
]}

Engel, Stanislav ^{[2
]}

Raaka, Bruce M. ^{[2
]}

Costanzi, Stefano ^{[1
]}

Gershengorn, Marvin C. ^{[2
]}

机构：

[1] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA

[2] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA

来源：

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

关键词：

D O I：

10.1021/jm7012425

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The G-protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches, and docking studies by using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions and provided important information on the role of specific amino acids in binding and activation of FFAR1.

引用

页码：625 / 633

页数：9

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