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Dual-targeted hit identification using pharmacophore screening

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Abstract

Mycobacterium tuberculosis infection remains a major cause of global morbidity and mortality due to the increase of antibiotics resistance. Dual/multi-target drug discovery is a promising approach to overcome bacterial resistance. In this study, we built ligand-based pharmacophore models and performed pharmacophore screening in order to identify hit compounds targeting simultaneously two enzymes—M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). In vitro aminoacylation assay revealed five compounds from different chemical classes inhibiting both enzymes. Among them the most active compound—3-(3-chloro-4-methoxy-phenyl)-5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-ylamine (1) inhibits mycobacterial LeuRS and MetRS with IC50 values of 13 µM and 13.8 µM, respectively. Molecular modeling study indicated that compound 1 has similar binding mode with the active sites of both aminoacyl-tRNA synthetases and can be valuable compound for further chemical optimization in order to find promising antituberculosis agents.

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Acknowledgements

This work was supported by the Science and Technology Center in Ukraine (Contract No. 6258) and by the National Academy of Sciences of Ukraine (Contract No. 80–10/04–2019). Authors are grateful to Dr. Stephen Cusack and Dr. Andres Palencia (EMBL Grenoble Outstation, France) for the gift of plasmid encoding M. tuberculosis LeuRS. We also thank Prof. Vasyl Mel’nyk (National Institute of Phthisiology and Pulmonology named after F.G. Yanovsky of the NAMS of Ukraine, Kyiv, Ukraine) for providing the gene encoding M. tuberculosis MetRS.

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Authors and Affiliations

  1. Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine

    Galyna P. Volynets, Sergiy A. Starosyla, Mariia Yu. Rybak, Volodymyr G. Bdzhola, Oksana P. Kovalenko, Vasyl S. Vdovin, Sergiy M. Yarmoluk & Michail A. Tukalo

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  1. Galyna P. Volynets
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  2. Sergiy A. Starosyla
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  3. Mariia Yu. Rybak
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  4. Volodymyr G. Bdzhola
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  5. Oksana P. Kovalenko
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  7. Sergiy M. Yarmoluk
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Correspondence to Galyna P. Volynets.

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Volynets, G.P., Starosyla, S.A., Rybak, M.Y. et al. Dual-targeted hit identification using pharmacophore screening. J Comput Aided Mol Des 33, 955–964 (2019). https://doi.org/10.1007/s10822-019-00245-5

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