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Discovery of Novel Agonists and Antagonists of the Free Fatty Acid Receptor 1 (FFAR1) Using Virtual Screening

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Laboratory of Biological Modeling, and Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
* Corresponding authors. (S.C.) E-mail: [email protected]. Phone: 301-451-7353 . Fax: 301-443-8000. (M.C.G.) E-mail: [email protected]. Phone: 301-496-4128 . Fax: 301-496-9943.
†Laboratory of Biological Modeling.
‡Clinical Endocrinology Branch.
§These authors have contributed equally to this work.
Cite this: J. Med. Chem. 2008, 51, 3, 625–633
Publication Date (Web):January 15, 2008
Copyright © This article not subject to U.S. Copyright. Published 2008 by the American Chemical Society

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    Abstract Image

    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.

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    Table enlisting the 52 compounds selected by virtual screening and experimentally tested. Docking poses of selected compounds at FFAR1. This material is available free of charge via the Internet at

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