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Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors

Lijun Song (UGent) , Romain Merceron (UGent) , Fabian Hulpia (UGent) , Ainhoa Lucia, Begona Gracia, Yanlin Jian, Martijn Risseeuw (UGent) , Toon Verstraelen (UGent) , Paul Cos, Jose A. Ainsa, et al.
(2021) EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 225.
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Abstract
Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. (C) 2021 Elsevier Masson SAS. All rights reserved.
Keywords
Mycobacterium tuberculosis, Thymidylate kinase, Structure-based inhibitor design, MYCOBACTERIUM-TUBERCULOSIS, DRUG-RESISTANCE, EFFLUX PUMP, GENERATION, VISUALIZATION, ACCUMULATION, PERMEABILITY, DISCOVERY, REVEALS, PHENOLS

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MLA
Song, Lijun, et al. “Structure-Aided Optimization of Non-Nucleoside M. Tuberculosis Thymidylate Kinase Inhibitors.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 225, 2021, doi:10.1016/j.ejmech.2021.113784.
APA
Song, L., Merceron, R., Hulpia, F., Lucia, A., Gracia, B., Jian, Y., … Van Calenbergh, S. (2021). Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 225. https://doi.org/10.1016/j.ejmech.2021.113784
Chicago author-date
Song, Lijun, Romain Merceron, Fabian Hulpia, Ainhoa Lucia, Begona Gracia, Yanlin Jian, Martijn Risseeuw, et al. 2021. “Structure-Aided Optimization of Non-Nucleoside M. Tuberculosis Thymidylate Kinase Inhibitors.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 225. https://doi.org/10.1016/j.ejmech.2021.113784.
Chicago author-date (all authors)
Song, Lijun, Romain Merceron, Fabian Hulpia, Ainhoa Lucia, Begona Gracia, Yanlin Jian, Martijn Risseeuw, Toon Verstraelen, Paul Cos, Jose A. Ainsa, I Boshoff, Helena, Helene Munier-Lehmann, Savvas Savvides, and Serge Van Calenbergh. 2021. “Structure-Aided Optimization of Non-Nucleoside M. Tuberculosis Thymidylate Kinase Inhibitors.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 225. doi:10.1016/j.ejmech.2021.113784.
Vancouver
1.
Song L, Merceron R, Hulpia F, Lucia A, Gracia B, Jian Y, et al. Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2021;225.
IEEE
[1]
L. Song et al., “Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors,” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 225, 2021.
@article{8728672,
  abstract     = {{Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. (C) 2021 Elsevier Masson SAS. All rights reserved.}},
  articleno    = {{113784}},
  author       = {{Song, Lijun and Merceron, Romain and Hulpia, Fabian and Lucia, Ainhoa and Gracia, Begona and Jian, Yanlin and Risseeuw, Martijn and Verstraelen, Toon and Cos, Paul and Ainsa, Jose A. and Boshoff, Helena, I and Munier-Lehmann, Helene and Savvides, Savvas and Van Calenbergh, Serge}},
  issn         = {{0223-5234}},
  journal      = {{EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}},
  keywords     = {{Mycobacterium tuberculosis,Thymidylate kinase,Structure-based inhibitor design,MYCOBACTERIUM-TUBERCULOSIS,DRUG-RESISTANCE,EFFLUX PUMP,GENERATION,VISUALIZATION,ACCUMULATION,PERMEABILITY,DISCOVERY,REVEALS,PHENOLS}},
  language     = {{eng}},
  pages        = {{25}},
  title        = {{Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors}},
  url          = {{http://doi.org/10.1016/j.ejmech.2021.113784}},
  volume       = {{225}},
  year         = {{2021}},
}
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