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Information × Registration Number 0220U104725, 0119U001863 , R & D reports Title Development of multitarget inhibitors for aminoacyl-tRNA synthetases using machine learning approaches to overcome Mycobacterium tuberculosis resistance to antibiotics popup.stage_title Head Volynets Halyna P., Кандидат біологічних наук Registration Date 26-12-2020 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description2  The models of artificial neural networks were generated and based on these models 40 compounds were selected for testing of their inhibitory activity toward Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). According to the results of testing 4 MetRS inhibitors and 1 LeuRS inhibitor decreasing the enzyme activity by more than 50% at the concentration of 100 µM were identified. According to the results of molecular docking, we have selected 41 derivatives of 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4] oxadiazole to study their inhibitory activity against M. tuberculosis LeuRS and MetRS and antibacterial activity against M. tuberculosis pathogenic strains. Recombinant M. tuberculosis LeuRS and MetRS in Esherichia coli cells in soluble form were obtained. The compounds inhibitory activity toward LeuRS and MetRS was investigated using aminoacylation assay. In vitro screening revealed 10 compounds active toward MetRS and 3 compounds active toward LeuRS. The structure-activity relationships for compounds in this chemical class was established. Antibacterial screening revealed 4 compounds active against mono-resistant strains of M. tuberculosis in the concentration range of 2-20 mg / l. Among these substances, only one compound - 3-(5-Chloro-2-methoxy-phenyl)-5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-ylamine, has significant inhibitory activity against mycobacterial MetRS. This compound is not cytotoxic toward HEK293 and HepG2 cell lines and may be promising for further chemical optimization and biological studies. Product Description popup.authors popup.nrat_date 2020-12-26 Close