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Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes
Author(s) -
Liu Renhe,
Lyu Xiaoxuan,
Batt Sarah M,
Hsu MeiHui,
Harbut Michael B,
Vilchèze Catherine,
Cheng Bo,
Ajayi Kehinde,
Yang Baiyuan,
Yang Yun,
Guo Hui,
Lin Changyou,
Gan Fei,
Wang Chen,
Franzblau Scott G.,
Jacobs William R.,
Besra Gurdyal S.,
Johnson Eric F.,
Petrassi Mike,
Chatterjee Arnab K.,
Fütterer Klaus,
Wang Feng
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201707324
Subject(s) - mycobacterium tuberculosis , tuberculosis , in vivo , in vitro , efflux , chemistry , computational biology , pharmacology , biochemistry , biology , genetics , medicine , pathology
Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X‐ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1–TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.