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Structure guided lead generation toward nonchiral M. tuberculosis thymidylate kinase inhibitors

(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(7). p.2753-2775
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Abstract
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
Keywords
DRUG-RESISTANT TUBERCULOSIS, MYCOBACTERIUM-TUBERCULOSIS, MONOPHOSPHATE KINASE, POTENT INHIBITORS, LIGAND EFFICIENCY, EFFLUX PUMP, CELL-WALL, DISCOVERY, AGENTS, PYRIMIDINE

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MLA
Song, Lijun, Romain Merceron, Begoña Gracia, et al. “Structure Guided Lead Generation Toward Nonchiral M. Tuberculosis Thymidylate Kinase Inhibitors.” JOURNAL OF MEDICINAL CHEMISTRY 61.7 (2018): 2753–2775. Print.
APA
Song, L., Merceron, R., Gracia, B., Quintana, A. L., Risseeuw, M., Hulpia, F., Cos, P., et al. (2018). Structure guided lead generation toward nonchiral M. tuberculosis thymidylate kinase inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 61(7), 2753–2775.
Chicago author-date
Song, Lijun, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Martijn Risseeuw, Fabian Hulpia, Paul Cos, et al. 2018. “Structure Guided Lead Generation Toward Nonchiral M. Tuberculosis Thymidylate Kinase Inhibitors.” Journal of Medicinal Chemistry 61 (7): 2753–2775.
Chicago author-date (all authors)
Song, Lijun, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Martijn Risseeuw, Fabian Hulpia, Paul Cos, José A Aínsa, Hélène Munier-Lehmann, Savvas Savvides, and Serge Van Calenbergh. 2018. “Structure Guided Lead Generation Toward Nonchiral M. Tuberculosis Thymidylate Kinase Inhibitors.” Journal of Medicinal Chemistry 61 (7): 2753–2775.
Vancouver
1.
Song L, Merceron R, Gracia B, Quintana AL, Risseeuw M, Hulpia F, et al. Structure guided lead generation toward nonchiral M. tuberculosis thymidylate kinase inhibitors. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(7):2753–75.
IEEE
[1]
L. Song et al., “Structure guided lead generation toward nonchiral M. tuberculosis thymidylate kinase inhibitors,” JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 7, pp. 2753–2775, 2018.
@article{8565559,
  abstract     = {In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.},
  author       = {Song, Lijun and Merceron, Romain and Gracia, Begoña and Quintana, Ainhoa Lucía and Risseeuw, Martijn and Hulpia, Fabian and Cos, Paul and Aínsa, José A and Munier-Lehmann, Hélène and Savvides, Savvas and Van Calenbergh, Serge},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keywords     = {DRUG-RESISTANT TUBERCULOSIS,MYCOBACTERIUM-TUBERCULOSIS,MONOPHOSPHATE KINASE,POTENT INHIBITORS,LIGAND EFFICIENCY,EFFLUX PUMP,CELL-WALL,DISCOVERY,AGENTS,PYRIMIDINE},
  language     = {eng},
  number       = {7},
  pages        = {2753--2775},
  title        = {Structure guided lead generation toward nonchiral M. tuberculosis thymidylate kinase inhibitors},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.7b01570},
  volume       = {61},
  year         = {2018},
}

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