Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/150996
Title: Target engagement and binding mode of an antituberculosis drug to its bacterial target deciphered in whole living cells by NMR
Authors: Bouvier, Guillaume
Simenel, Catherine
Jang, Jichan
Kalia, Nitin P.
Choi, Inhee
Nilges, Michael
Pethe, Kevin
Izadi-Pruneyre, Nadia
Keywords: Science::Biological sciences
Issue Date: 2018
Source: Bouvier, G., Simenel, C., Jang, J., Kalia, N. P., Choi, I., Nilges, M., Pethe, K. & Izadi-Pruneyre, N. (2018). Target engagement and binding mode of an antituberculosis drug to its bacterial target deciphered in whole living cells by NMR. Biochemistry, 58(6), 526-533. https://dx.doi.org/10.1021/acs.biochem.8b00975
Project: NMRC/CBRG/0083/2015
Journal: Biochemistry
Abstract: Detailed information on hit–target interaction is very valuable for drug discovery efforts and indispensable for rational hit to lead optimization. We developed a new approach combining NMR in whole-cells in-cell NMR) and docking to characterize hit–target interaction at the atomic level. By using in-cell NMR, we validated target engagement of the antituberculosis imidazopyridine amide (IPA) series with the subunit b of the cytochrome bc1:aa3, the major respiratory terminal oxidase in mycobacteria. The most advanced IPA called Q203 is currently in clinical trial. Using its derivative IPA317, we identified the atoms of the drug interacting with the cytochrome b in whole cells. NMR data and the self-organizing map algorithm were used to cluster a large set of drug–target complex models. The selected ensemble revealed IPA317 in a transient cavity of the cytochrome b, interacting directly with the residue T313, which is the site of spontaneous mutation conferring resistance to the IPA series. Our approach constitutes a pipeline to obtain atomic information on hit–target interactions in the cellular context.
URI: https://hdl.handle.net/10356/150996
ISSN: 0006-2960
DOI: 10.1021/acs.biochem.8b00975
Rights: © 2018 American Chemical Society. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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