Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

Title
Unique binding mode of Evogliptin with human dipeptidyl peptidase IV
Authors
김은경이형기김미경김하동김흥재김지원이지오김찬화
Keywords
Dipeptidyl peptidase IV; DPP4; Evogliptin; Diabetes; Inhibitor; Complex structure
Issue Date
2017-12
Publisher
Biochemical and biophysical research communications
Citation
VOL 494, NO 3-4-459
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.
URI
http://pubs.kist.re.kr/handle/201004/66718
ISSN
0006-291X
Appears in Collections:
KIST Publication > Article
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