Lee, Hyung Ki Kim, Mi-Kyung Kim, Ha Dong Kim, Heung Jae Kim, Ji Won Lee, Jie-Oh Kim, Chan-Wha Kim, Eunice EunKyeong 2024-01-20T00:00:28Z 2024-01-20T00:00:28Z 2021-09-03 2017-12-16 0006-291X https://pubs.kist.re.kr/handle/201004/121911 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. English ACADEMIC PRESS INC ELSEVIER SCIENCE HIGHLY POTENT PRECLINICAL PROFILE INHIBITOR DISCOVERY SYSTEM Unique binding mode of Evogliptin with human dipeptidyl peptidase IV Article 10.1016/j.bbrc.2017.10.101 1 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.494, no.3-4, pp.452 - 459 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 494 3-4 452 459 scie scopus 000416393300005 2-s2.0-85032980700 Biochemistry & Molecular Biology Biophysics Biochemistry & Molecular Biology Biophysics Article HIGHLY POTENT PRECLINICAL PROFILE INHIBITOR DISCOVERY SYSTEM Dipeptidyl peptidase IV DPP4 Evogliptin Diabetes Inhibitor Complex structure