Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

Renhe Liu, Xiaoxuan Lyu, Sarah Batt, Meihui Hsu, Michael B Harbut, Catherine Vilcheze, Bo Cheng, Kehinde Ajayi, Baiyuan Yang, Yun Yang, Hui Guo, Changyou Lin, Fei Gan, Chen Wang, Scott G Franzblau, William R Jacobs Jr., Gurdyal Besra, Eric F Johnson, Mike Petrassi, Arnab K ChatterjeeKlaus Futterer, Feng Wang

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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.
Original languageEnglish
Pages (from-to)13011–13015
JournalAngewandte Chemie (International Edition)
Issue number42
Early online date15 Aug 2017
Publication statusPublished - 7 Sept 2017


  • DprE1
  • CYP2C9
  • anti-tubercular drugs
  • drug-drug interactions
  • drug development


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