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

• Published in: Journal of medicinal chemistry Vol. 51; no. 3; pp. 625 - 633
• Main Authors: Tikhonova, Irina G, Sum, Chi Shing, Neumann, Susanne, Engel, Stanislav, Raaka, Bruce M, Costanzi, Stefano, Gershengorn, Marvin C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 14.02.2008
• Subjects: 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; 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm7012425

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.