Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

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

Research output: Contribution to journalArticle

Abstract

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 (US)
Pages (from-to)13011-13015
Number of pages5
JournalAngewandte Chemie - International Edition
Volume56
Issue number42
DOIs
StatePublished - Oct 9 2017

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Bacterial Drug Resistance
Antitubercular Agents
Thiophenes
Biochemistry
Bacterial Proteins
X ray crystallography
X Ray Crystallography
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Structure-Activity Relationship
Mycobacterium tuberculosis
Catalytic Domain
Animals
Tuberculosis
Crystal structure
Binding Sites
Lead compounds
Isomerases
Biosynthesis
Cell Wall

Keywords

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

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Cite this

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. / Liu, Renhe; Lyu, Xiaoxuan; Batt, Sarah M.; Hsu, Mei Hui; 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.

In: Angewandte Chemie - International Edition, Vol. 56, No. 42, 09.10.2017, p. 13011-13015.

Research output: Contribution to journalArticle

Liu, R, Lyu, X, Batt, SM, Hsu, MH, Harbut, MB, Vilchèze, C, Cheng, B, Ajayi, K, Yang, B, Yang, Y, Guo, H, Lin, C, Gan, F, Wang, C, Franzblau, SG, Jacobs, WR, Besra, GS, Johnson, EF, Petrassi, M, Chatterjee, AK, Fütterer, K & Wang, F 2017, 'Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes', Angewandte Chemie - International Edition, vol. 56, no. 42, pp. 13011-13015. https://doi.org/10.1002/anie.201707324
Liu, Renhe ; Lyu, Xiaoxuan ; Batt, Sarah M. ; Hsu, Mei Hui ; 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. / Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. In: Angewandte Chemie - International Edition. 2017 ; Vol. 56, No. 42. pp. 13011-13015.
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