Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.

Autor: Liu R; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Lyu X; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Batt SM; School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK., Hsu MH; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Harbut MB; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Vilchèze C; Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, UK., Cheng B; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Ajayi K; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Yang B; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Yang Y; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Guo H; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Lin C; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Gan F; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Wang C; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Franzblau SG; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois, Chicago, IL, 60612, USA., Jacobs WR Jr; Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, UK., Besra GS; School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK., Johnson EF; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA., Petrassi M; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Chatterjee AK; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA., Fütterer K; School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK., Wang F; California Institute for Biomedical Research (Calibr), La Jolla, CA, 92037, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2017 Oct 09; Vol. 56 (42), pp. 13011-13015. Date of Electronic Publication: 2017 Sep 07.
DOI: 10.1002/anie.201707324
Abstrakt: 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.
(© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
Databáze: MEDLINE
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