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Information × Registration Number 0224U032962, (0124U004174) , R & D reports Title Investigation of Mycobacterium tuberculosis leucyl-tRNA synthetase structural features for rational drug design popup.stage_title Дослідження структурних особливостей лейцил-тРНК синтетази (ЛейРС) Mycobacterium tuberculosis за допомогою методу молекулярної динаміки та дизайн інгібіторів цього ензиму з використанням рецепторно-орієнтованого віртуального скринінгу Head Yarmoluk Serhii M., Доктор хімічних наук Registration Date 12-12-2024 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description1 The aim of the Project is investigation of structural features of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) using the methods of molecular dynamics, site-directed mutagenesis and cryo-electron microscopy (cryo-EM) and development of small-molecular inhibitors as potential antituberculosis agents popup.description2 Molecular dynamics (MD) simulation of the complex of M. tuberculosis LeuRS with leucyl-adenylate analogue was carried out during 20 ns using GROMACS 4.5 software package. According to the calculation results, two conformations of aminoacyl-tRNA synthetase were selected for molecular docking – at 2196 ps and 15816 ps of MD simulation, which are characterized by low values of the sum of the electrostatic and van der Waals energies of the complex. Molecular docking of compound collection containing 253,838 ligands, into the synthetic site of M. tuberculosis LeuRS selected conformations was performed using the DOCK 4.0 software package. 214 compounds were selected for testing of inhibitory activity toward recombinant M. tuberculosis LeuRS using tRNA aminoacylation assay. Recombinant M. tuberculosis LeuRS was obtained in sufficient amount. As a result of biochemical screening of compounds toward recombinant enzyme, we have identified highly effective inhibitors of mycobacterial LeuRS among the derivatives of N-(5-benzyl-thiazol-2-yl)-2-(4-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide, which inhibit the activity of the enzyme by more than 90% at a concentration of 100 µM. For the four the most active compounds – N-[5-(2-(Chloro-benzyl)-thiazol-2-yl]-2-(4-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide (compound 1), N-(5-benzyl-thiazol-2-yl)-2-(4-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide (compound 2), N-(5-benzyl-thiazol-2-yl)-2-[4-(4-methoxy-phenyl)-1H-tetrazol-5-ylsulfanyl]-acetamide (compound 3), N-[5-(2,6-dichloro-benzyl)-thiazol-2-yl]-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide (compound 4) the IC50 values were established, which were 7.73 µM, 28.07 µM, 12.45 µM and 13.39 µM, respectively.   Product Description popup.authors popup.nrat_date 2024-12-12 Close