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https://hdl.handle.net/10356/163131
Title: | Binding properties of the anti-TB drugs bedaquiline and TBAJ-876 to a mycobacterial F-ATP synthase | Authors: | Krah, Alexander Grüber, Gerhard Bond, Peter. J. |
Keywords: | Science::Biological sciences::Biophysics | Issue Date: | 2022 | Source: | Krah, A., Grüber, G. & Bond, P. J. (2022). Binding properties of the anti-TB drugs bedaquiline and TBAJ-876 to a mycobacterial F-ATP synthase. Current Research In Structural Biology, 4, 278-284. https://dx.doi.org/10.1016/j.crstbi.2022.09.001 | Project: | NRF-CRP18-2017-01 | Journal: | Current Research In Structural Biology | Abstract: | Tuberculosis (TB), the deadly disease caused by Mycobacterium tuberculosis (Mtb), kills more people worldwide than any other bacterial infectious disease. There has been a recent resurgence of TB drug discovery activities, resulting in the identification of a number of novel enzyme inhibitors. Many of these inhibitors target the electron transport chain complexes and the F1FO-ATP synthase; these enzymes represent new target spaces for drug discovery, since the generation of ATP is essential for the bacterial pathogen’s physiology, persistence, and pathogenicity. The anti-TB drug bedaquiline (BDQ) targets the Mtb F-ATP synthase and is used as salvage therapy against this disease. Medicinal chemistry efforts to improve the physio-chemical properties of BDQ resulted in the discovery of 3,5-dialkoxypyridine (DARQ) analogues to which TBAJ-876 belongs. TBAJ-876, a clinical development candidate, shows attractive in vitro and in vivo antitubercular activity. Both BDQ and TBAJ-876 inhibit the mycobacterial F1FO-ATP synthase by stopping rotation of the c-ring turbine within the FO domain, thereby preventing proton translocation and ATP synthesis to occur. While structural data for the BDQ bound state are available, no structural information about TBAJ-876 binding have been described. In this study, we show how TBAJ-876 binds to the FO domain of the M. smegmatis F1FO-ATP synthase. We further calculate the binding free energy of both drugs bound to their target and predict an increased affinity of TBAJ-876 for the FO domain. This approach will be useful in future efforts to design new and highly potent DARQ analogs targeting F-ATP synthases of Mtb, nontuberculosis mycobacteria (NTM) as well as the M. leprosis complex. | URI: | https://hdl.handle.net/10356/163131 | ISSN: | 2665-928X | DOI: | 10.1016/j.crstbi.2022.09.001 | Rights: | © 2022 The Authors. All rights reserved. This paper was published by Elsevier B.V. in Current Research in Structural Biology and is made available with permission of The Authors. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Journal Articles |
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BDQ_ATP_synthase_Curr Res Struct Biology.pdf | 1.35 MB | Adobe PDF | View/Open |
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