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Information × Registration Number 0220U101517, 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 Registration Date 12-02-2020 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description2  During performing the Project, the ligand-based pharmacophore models were built based on the structures of known leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS) inhibitors from different microorganisms. According to the results of pharmacophore screening, 156 compounds were selected for the study of their inhibitory activity toward Mycobacterium tuberculosis LeuRS and MetRS. Recombinant LeuRS and MetRS were obtained in Esherichia coli. Testing of compounds inhibitory activity toward LeuRS and MetRS was performed using aminoacylation assay. Among them we have found five small-molecular inhibitors that were simultaneously active toward mycobacterial LeuRS and MetRS. 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 inhibits the activity of mycobacterial LeuRS and MetRS with IC50 values of 13 µM and 13.8 µM, respectively. Cross docking of the library containing 129 derivatives of 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole was performed into the active sites of M. tuberculosis LeuRS and MetRS. According to the results of virtual screening, 47 compounds from these chemical class were selected for testing of their inhibitory activity toward recombinant LeuRS and MetRS. Among them, 6 compounds inhibiting activity of both M. tuberculosis LeuRS and MetRS were identified. The models of artificial neural networks were built, which will be used for further virtual screening. Product Description popup.authors Volynets Halyna P. Protopopov Mykola V. Rybak Mariia Yu. Starosyla Sergiy A. popup.nrat_date 2020-04-02 Close