Discovery of Novel Agonists and Antagonists of the Free Fatty Acid Receptor 1 (FFAR1) Using Virtual Screening
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-dim...
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Published in | Journal of medicinal chemistry Vol. 51; no. 3; pp. 625 - 633 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
14.02.2008
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Abstract | 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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AbstractList | 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. |
Author | Gershengorn, Marvin C Tikhonova, Irina G Costanzi, Stefano Sum, Chi Shing Neumann, Susanne Engel, Stanislav Raaka, Bruce M |
Author_xml | – sequence: 1 givenname: Irina G surname: Tikhonova fullname: Tikhonova, Irina G – sequence: 2 givenname: Chi Shing surname: Sum fullname: Sum, Chi Shing – sequence: 3 givenname: Susanne surname: Neumann fullname: Neumann, Susanne – sequence: 4 givenname: Stanislav surname: Engel fullname: Engel, Stanislav – sequence: 5 givenname: Bruce M surname: Raaka fullname: Raaka, Bruce M – sequence: 6 givenname: Stefano surname: Costanzi fullname: Costanzi, Stefano email: stefanoc@mail.nih.gov, marving@intra.niddk.nih.gov – sequence: 7 givenname: Marvin C surname: Gershengorn fullname: Gershengorn, Marvin C email: stefanoc@mail.nih.gov, marving@intra.niddk.nih.gov |
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Keywords | Agonist GPR40 receptor Thiazole derivatives Site directed mutagenesis Virtual screening Free fatty acid Insulin Structure function relationship Non steroidal antiinflammatory agent Benzoic acid derivatives Structure activity relation G protein coupled receptor Binding mode Carboxamide Arylpropionic acid derivatives Benzamide derivatives Antagonist G protein |
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Notes | 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 http://pubs.acs.org. ark:/67375/TPS-TVFR3F49-B istex:09792D9E9C9EB29D58AC7A379F60E07AFC7A16A8 |
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Snippet | 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... |
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SubjectTerms | Binding Sites Biological and medical sciences Calcium - metabolism Cell Line Databases, Factual Drug Partial Agonism General and cellular metabolism. Vitamins Humans Ligands Medical sciences Mutation Pharmacology. Drug treatments Protein Conformation Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - chemistry Stereoisomerism Structure-Activity Relationship Thiadiazoles - chemistry Thiadiazoles - pharmacology Thiazolidines - chemistry Thiazolidines - pharmacology |
Title | Discovery of Novel Agonists and Antagonists of the Free Fatty Acid Receptor 1 (FFAR1) Using Virtual Screening |
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