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Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening

Abstract

Decaprenylphosphoryl-β-D-ribose oxidase (DprE1) plays important roles in the biosynthesis of mycobacterium cell wall. DprE1 inhibitors have shown great potentials in the development of new regimens for tuberculosis (TB) treatment. In this study, an integrated molecular modeling strategy, which combined computational bioactivity fingerprints and structure-based virtual screening, was employed to identify potential DprE1 inhibitors. Two lead compounds (B2 and H3) that could inhibit DprE1 and thus kill Mycobacterium smegmatis in vitro were identified. Moreover, compound H3 showed potent inhibitory activity against Mycobacterium tuberculosis in vitro (MICMtb = 1.25 μM) and low cytotoxicity against mouse embryo fibroblast NIH-3T3 cells. Our research provided an effective strategy to discover novel anti-TB lead compounds.

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Fig. 1: Virtual screening and preliminary biological evaluation.
Fig. 2: B2 and H3 are potent DprE1 inhibitors.
Fig. 3: Cytotoxicity and key residues in DprE1 for the binding of sulfonamide series compounds.
Fig. 4: Binding mode analysis and in vitro antitubercular activity of compound H3 against Mtb H37Ra.

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Acknowledgements

This work was financially supported by Natural Science Foundation of China of Zhejiang Province (LZ19H300001), National Natural Science Foundation of China (21907084, 81302679, 81973372, 21920102003), Fundamental Research Funds for the Central Universities (2020QNA7003), and “Double Top-Class” University Project (181201*194232101).

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Authors

Contributions

TJH, DL and DSC initiated and supervised the research. XPH and LY designed the experiments. XPH and LY conducted virtual screening, compound validations and biological assays. XC, YXL, MSA, CS, DJJ, ZW, ZYL, LX, KLW, TYZ, and YLY helped performing part of biological assays. LL helped performing the CBFP-based similarity search. XPH, LY, DL and TJH wrote the manuscript, and the other authors contributed specific parts of the manuscript. TJH, DL and DSC assume responsibility for the manuscript in its entirety. All authors have critically revised the manuscript and approved its final version.

Corresponding authors

Correspondence to Dan Li, Dong-sheng Cao or Ting-jun Hou.

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The authors declare no competing interests.

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Hu, Xp., Yang, L., Chai, X. et al. Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00779-1

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Keywords

  • molecular docking
  • virtual screening
  • DprE1
  • tuberculosis
  • covalent inhibitors

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