Discovery of novel agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening

J Med Chem. 2008 Feb 14;51(3):625-33. doi: 10.1021/jm7012425. Epub 2008 Jan 15.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Binding Sites
  • Calcium / metabolism
  • Cell Line
  • Databases, Factual
  • Drug Partial Agonism
  • Humans
  • Ligands
  • Mutation
  • 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


  • FFAR1 protein, human
  • Ligands
  • Receptors, G-Protein-Coupled
  • Thiadiazoles
  • Thiazolidines
  • Calcium