Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6)

J Med Chem. 2016 Sep 8;59(17):8094-102. doi: 10.1021/acs.jmedchem.6b00869. Epub 2016 Aug 18.

Abstract

Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.

MeSH terms

  • Bile Acids and Salts / chemistry*
  • Binding Sites
  • Crystallography, X-Ray
  • Fatty Acid-Binding Proteins / antagonists & inhibitors
  • Fatty Acid-Binding Proteins / chemistry*
  • Gastrointestinal Hormones / antagonists & inhibitors
  • Gastrointestinal Hormones / chemistry*
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Structure-Activity Relationship
  • Surface Plasmon Resonance
  • Taurocholic Acid / chemistry

Substances

  • Bile Acids and Salts
  • Fatty Acid-Binding Proteins
  • Gastrointestinal Hormones
  • fatty acid-binding protein 6
  • Taurocholic Acid