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

Irina G. Tikhonova, Chi Shing Sum, Susanne Neumann, Stanislav Engel, Bruce M. Raaka, Stefano Costanzi, Marvin C. Gershengorn

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)625-633
Number of pages9
JournalJournal of Medicinal Chemistry
Volume51
Issue number3
DOIs
Publication statusPublished - 14 Feb 2008

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening'. Together they form a unique fingerprint.

Cite this