期刊
BIOCHEMISTRY
卷 58, 期 6, 页码 526-533出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.8b00975
关键词
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资金
- Institut Pasteur
- Centre National de la Recherche Scientifique (CNRS)
- Fondation pour la Recherche Medicale [Equipe FRM 2017M.DEQ20170839114]
- ERC [FP7-IDEAS-ERC 294809]
- National Research foundation of Korea (NRF) - Korea government (MSIT), Gyeonggi-do [NRF-2017M3A9G6068257]
- Singapore Ministry of Health's National Medical Research Council [NMRC/CBRG/0083/2015]
- French Region Ile de France through the SESAME 2014 NMRCHR program [14014526]
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 anti- Bacteria l cells tuberculosis imidazopyridine amide (IPA) series with the subunit b of the cytochrome bc(1):aa(3), 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.
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