title: Discovery of novel agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening.
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.
authors.affiliation: Laboratory of Biological Modeling, and Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Chi Shing
authors.initials: CS
authors.lastname: Sum
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.forename: Stanislav
authors.initials: S
authors.lastname: Engel
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Raaka
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016208:Databases, Factual; D054333:Drug Partial Agonism; D006801:Humans; D008024:Ligands; D009154:Mutation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C473034:FFAR1 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D013830:Thiadiazoles; D053778:Thiazolidines; D002118:Calcium