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Targeting Tuberculosis: Novel Scaffolds for Inhibiting Cytochrome bd Oxidase
Open accessPreprint — published as 10.1021/acs.jcim.4c00344 · Paper page
Abstract
Discovered in the 1920s, cytochrome bd is a terminal oxidase that has received renewed attention as a drug target since its atomic structure was first solved in 2016. Only found in prokaryotes, we study it here as a drug target for Mycobacterium tuberculosis ( Mtb ). Most previous drug discovery efforts towards cytochrome bd have involved analogs of the canonical substrate quinone, known as Aurachin D. Here we report six new cytochrome bd inhibitor scaffolds determined from a computational screen totaling over one million molecules and confirmed on target activity through in vitro testing. These scaffolds provide new avenues for lead optimization towards Mtb therapeutics.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Research works printed but not linked: 46
- 10.1089/ars.2020.8039 · DOI
- 10.1126/science.aaf5514 · DOI
- 2022, Recent advances in structural studies of cytochrome bd and its potential application as a drug target, International Journal of Molecular Sciences, 23, 3166, 10.3390/ijms23063166 · DOI
- 1928, On the respiratory pigment, cytochrome, in bacteria, Proceedings of the Imperial Academy, 4, 436, 10.2183/pjab1912.4.436 · DOI
- 10.1126/science.aaf2477 · DOI
- 10.1126/science.aay0967 · DOI
- 2019, Homologous bd oxidases share the same architecture but differ in mechanism, Nature communications, 10, 5138, 10.1038/s41467-019-13122-4 · DOI
- 2021, Structure of Escherichia coli cytochrome bd-II type oxidase with bound aurachin D, Nature Communications, 12, 6498, 10.1038/s41467-021-26835-2 · DOI
- 10.1073/pnas.2114013118 · DOI
- 2021, The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB, Nature Communications, 12, 5236, 10.1038/s41467-021-25537-z · DOI
- 2021, Cryo-EM structure of mycobacterial cytochrome bd reveals two oxygen access channels, Nature Communications, 12, 4621, 10.1038/s41467-021-24924-w · DOI
- 10.1021/bi00003a044 · DOI
- 2015, The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress, Scientific reports, 5, 10333, 10.1038/srep10333 · DOI
- 2021, Short-chain aurachin D derivatives are selective inhibitors of E. coli cytochrome bd-I and bd-II oxidases, Scientific Reports, 11, 23852, 10.1038/s41598-021-03288-7 · DOI
- 10.1093/oxfordjournals.jbchem.a022250 · DOI
- 2023, Identification of 2-Aryl-Quinolone Inhibitors of Cytochrome bd and Chemical Validation of Combination Strategies for Respiratory Inhibitors against Mycobacterium tuberculosis, ACS Infectious Diseases, 9, 221, 10.1021/acsinfecdis.2c00283 · DOI
- 2023, Discovery of 1-hydroxy-2-methylquinolin-4 (1H)-one derivatives as new cytochrome bd oxidase inhibitors for tuberculosis therapy, European Journal of Medicinal Chemistry, 245, 114896, 10.1016/j.ejmech.2022.114896 · DOI
- 2022, Design, synthesis and biological evaluation of (Quinazoline 4-yloxy) acetamide and (4-oxoquinazoline-3 (4H)-yl) acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase, European Journal of Medicinal Chemistry, 242, 114639, 10.1016/j.ejmech.2022.114639 · DOI
- 2022, Synthesis and biological evaluation of aurachin D analogues as inhibitors of Mycobacterium tuberculosis cytochrome bd oxidase, ACS Medicinal Chemistry Letters, 13, 1663, 10.1021/acsmedchemlett.2c00401 · DOI
- 2021, Identification and optimization of quinolone-based inhibitors against cytochrome bd oxidase using an electrochemical assay, Electrochimica Acta, 381, 138293, 10.1016/j.electacta.2021.138293 · DOI
- 10.1007/s11030-020-10034-0 · DOI
- 2021, Structure guided generation of thieno [3, 2-d] pyrimidin-4-amine Mycobacterium tuberculosis bd oxidase inhibitors, RSC Medicinal Chemistry, 12, 73, 10.1039/D0MD00398K · DOI
- 2021, Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis, EMBO Molecular Medicine, 13, e13207, 10.15252/emmm.202013207 · DOI
- 2022, An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis, Communications Biology, 5, 166, 10.1038/s42003-022-03110-8 · DOI
- 10.1039/D3MD00587A · DOI
- Harikishore, A. ; Mathiyazakan, V. ; Pethe, K. ; Grüber, G. Novel targets and inhibitors of the Mycobacterium tuberculosis cytochrome bd oxidase to foster anti-tuberculosis drug discovery. Expert Opinion on Drug DiscSovery 2023, 1–11. · DOI
- 2015, Gaussian accelerated molecular dynamics: Unconstrained enhanced sampling and free energy calculation, Journal of chemical theory and computation, 11, 3584, 10.1021/acs.jctc.5b00436 · DOI
- 10.1016/bs.arcc.2017.06.005 · DOI
- 2021, Gaussian accelerated molecular dynamics: Principles and applications, Wiley Interdisciplinary Reviews: Computational Molecular Science, 11, e1521
- 2021, Data for molecular dynamics simulations of Escherichia coli cytochrome bd oxidase with the Amber force field, Data in Brief, 38, 107401, 10.1016/j.dib.2021.107401 · DOI
- 2011, PROPKA3: consistent treatment of internal and surface residues in empirical p K a predictions, Journal of chemical theory and computation, 7, 525, 10.1021/ct100578z · DOI
- 10.1002/jcc.21287 · DOI
- 10.1002/jcc.20945 · DOI · Paper page
- 10.1074/jbc.271.12.6801 · DOI
- 1979, Asymmetric distribution of phospholipids in membranes from Mycobacterium phlei, Archives of Biochemistry and Biophysics, 198, 22, 10.1016/0003-9861(79)90391-6 · DOI
- 10.1016/S0065-2911(08)60016-8 · DOI
- 10.1074/jbc.M004658200 · DOI
- Daffé, M. ; Marrakchi, H. Unraveling the structure of the mycobacterial envelope. Microbiology spectrum 2019, 7 (4), 7.4.1. · DOI
- 10.1063/1.445869 · DOI
- 10.1063/1.466711 · DOI
- 2015, ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB, Journal of chemical theory and computation, 11, 3696, 10.1021/acs.jctc.5b00255 · DOI
- 10.1002/jcc.20035 · DOI
- 2014, POVME 2.0: an enhanced tool for determining pocket shape and volume characteristics, Journal of chemical theory and computation, 10, 5047, 10.1021/ct500381c · DOI
- 2018, Pyrazolo [1, 5-a] pyridine inhibitor of the respiratory cytochrome bcc complex for the treatment of drug-resistant tuberculosis, ACS infectious diseases, 5, 239
- 10.1073/pnas.1612353113 · DOI
- 10.1109/MCSE.2014.80 · DOI
Metadata
- Authors
- Seitz, C., Ahn, S.-H., Wei, H., Kyte, M., Cook, G. M., Krause, K., & McCammon, J. A.
- Affiliations
- University of California San Diego (US)
- University of California, Davis (US)
- University of Otago (NZ)
- Corresponding author
- Seitz, Christian
- Ahn, Surl-Hee
- Krause, Kurt
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- openRxiv
- Published
- 2024-02-29
- Volume
- 64
- Issue
- 13
- Pages
- 5232-5241
- ISSN
- 1549-9596 (ISSN-L)
- OpenAlex
- W4399671402
- Cited by
- 11
- References
- 1
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Journal of Chemical Information and Modeling (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Science Foundation (1650112, 1548562)
- San Diego Supercomputer Center
- Royal Society Te Apārangi (UOO1702)
- University of California, Davis
- Health Research Council of New Zealand (23/396)
- Marsden Fund (UOO1603)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Keywords
- cytochrome bd oxidase, Mycobacterium tuberculosis, tuberculosis drug targets, lead optimization
- MeSH terms
- Antitubercular Agents, Enzyme Inhibitors, Models, Molecular, Mycobacterium tuberculosis, Oxidoreductases, Tuberculosis, Molecular Docking Simulation
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