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

doi:10.1016/j.bbrc.2017.10.101

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

Department of Biotechnology

Research output: Contribution to journal › Article › peer-review

8 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 language	English
Pages (from-to)	452-459
Number of pages	8
Journal	Biochemical and Biophysical Research Communications
Volume	494
Issue number	3-4
DOIs	https://doi.org/10.1016/j.bbrc.2017.10.101
Publication status	Published - 2017 Dec 16

Keywords

Complex structure
Diabetes
Dipeptidyl peptidase IV
DPP4
Evogliptin
Inhibitor

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2017.10.101

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title = "Unique binding mode of Evogliptin with human dipeptidyl peptidase IV",

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, Diabetes, Dipeptidyl peptidase IV, DPP4, Evogliptin, Inhibitor",

author = "Lee, {Hyung Ki} and Kim, {Mi Kyung} and Kim, {Ha Dong} and Kim, {Heung Jae} and Kim, {Ji Won} and Lee, {Jie Oh} and Kim, {Chan Wha} and Kim, {Eunice Eun Kyeong}",

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AU - Lee, Hyung Ki

AU - Kim, Mi Kyung

AU - Kim, Ha Dong

AU - Kim, Heung Jae

AU - Kim, Ji Won

AU - Lee, Jie Oh

AU - Kim, Chan Wha

AU - Kim, Eunice Eun Kyeong

PY - 2017/12/16

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AB - 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.

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KW - Inhibitor

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Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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