Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

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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 S-1 pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S-2 extensive subsite, and that the multiple hydrogen bonds made by the (R)-beta-amine group in the S-2 pocket and the contacts made by the (R)-tert-butyl group with Arg125 contribute to the high potency observed for Evogliptin. (c) 2017 Elsevier Inc. All rights reserved.
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Issue Date
2017-12
Language
English
Article Type
Article
Keywords

HIGHLY POTENT; PRECLINICAL PROFILE; INHIBITOR; DISCOVERY; SYSTEM

Citation

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.494, no.3-4, pp.452 - 459

ISSN
0006-291X
DOI
10.1016/j.bbrc.2017.10.101
URI
http://hdl.handle.net/10203/237153
Appears in Collection
CH-Journal Papers(저널논문)
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