Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):452-459. doi: 10.1016/j.bbrc.2017.10.101. Epub 2017 Oct 20.

Abstract

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (S,R diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S1 pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S2 extensive subsite, and that the multiple hydrogen bonds made by the (R)-β-amine group in the S2 pocket and the contacts made by the (R)-tert-butyl group with Arg125 contribute to the high potency observed for Evogliptin.

Keywords: Complex structure; DPP4; Diabetes; Dipeptidyl peptidase IV; Evogliptin; Inhibitor.

MeSH terms

  • Binding Sites
  • Dipeptidyl Peptidase 4 / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Enzyme Activation
  • Humans
  • Models, Chemical*
  • Models, Molecular*
  • Piperazines / chemistry*
  • Protein Binding

Substances

  • 4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one
  • Dipeptidyl-Peptidase IV Inhibitors
  • Piperazines
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4