Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

Hyung Ki Lee, Mi Kyung Kim, Ha Dong Kim, Heung Jae Kim, Ji Won Kim, Jie Oh Lee, Chan Wha Kim, Eunice Eun Kyeong Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)452-459
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume494
Issue number3-4
DOIs
Publication statusPublished - 2017 Dec 16

Keywords

  • Complex structure
  • Diabetes
  • Dipeptidyl peptidase IV
  • DPP4
  • Evogliptin
  • Inhibitor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Lee, H. K., Kim, M. K., Kim, H. D., Kim, H. J., Kim, J. W., Lee, J. O., Kim, C. W., & Kim, E. E. K. (2017). Unique binding mode of Evogliptin with human dipeptidyl peptidase IV. Biochemical and Biophysical Research Communications, 494(3-4), 452-459. https://doi.org/10.1016/j.bbrc.2017.10.101