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

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 2D-similarity, 3D-pharmacophore searches and docking studies, 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.