Biopolym. Cell. 2026; 42(3):171-181.
https://doi.org/10.7124/bc.000BB8
Molecular and Cell Biotechnologies
Discovery of a novel hit compound targeting Mycobacterium tuberculosis Leucyl-tRNA synthetase
1, 2Volynets G. P., 1Usenko M. O., 1Skydanovych O. I., 1Gorbatiuk O. B., 1Bdzhola V. G., 1Lukashov S. S., 1Borovykov O. V., 1Kotey I. M., 1Antonenko S. V., 1Marchenko S. V., 1Yarmoluk S. M., 1Tukalo M. A.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  2. LLC “Scientific and service firm “Otava”
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143

Abstract

Aim. The objective of this study was to develop novel hit compounds targeting Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS). Methods. Molecular docking was carried out using DOCK 4.0 software. The recombinant mycobacterial LeuRS was expressed in Escherichia coli Rosetta (DE3) cells and subsequently purified. The inhibitory activity of compounds toward recombinant M. tuberculosis LeuRS was assessed using an aminoacylation assay with BIOMOL® Green reagent. The IC50 value of the most active compound was measured in aminoacylation assay using 14C-labeled L-leucine. Results. Based on our previously reported results of a 20 ns molecular dynamics (MD) simulation of the complex of M. tuberculosis LeuRS with a leucyl-adenylate analogue, the frame at 15,816 ps, corresponding to the lowest interaction energy of the complex, was selected for subsequent molecular docking studies. According to the molecular docking data for a library comprising 253,838 compounds, 70 compounds were selected for investigation of their inhibitory activity toward recombinant M. tuberculosis LeuRS. Among them 10 compounds inhibited activity of recombinant M. tuberculosis LeuRS by 30-65% at the concentration of 100 μM. The IC50 value of the most active compound – 4,4,4-trifluoro-2-[1-hydroxy-4-(2-oxo-1,2-dihydro-benzo[cd]indole-6-sulfonylamino)-naphthalen-2-yl]-3-oxo-butyric acid isopropyl ester was 49.6 μM. Conclusions. Therefore, using the combination of computer modeling techniques and biochemical screening experiments the novel hit compound targeting M. tuberculosis LeuRS was identified which can be used for further chemical optimization and biological research.
Keywords: Mycobacterium tuberculosis, leucyl-tRNA synthetase, LeuRS, molecular dynamics, molecular docking, inhibitor
Full text: (PDF, in English)

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