0099 In silico identification of natural product inhibitors of Brucella abortus threonyl-tRNA synthetase

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Bovine brucellosis is mainly caused by the bacterium Brucella abortus, and represents a major problem to livestock industry development worldwide and is also a threat to human health in many developing and underdeveloped countries. Aminoacyl-tRNA synthetases (aaRSs), the central enzymes in protein translation, catalyze the covalent attachment of correct amino acids to their cognate tRNAs, yielding the aminoacyl tRNAs (aa-tRNA or charged tRNA) used for protein synthesis. Due to the pivotal role in protein synthesis, aaRSs have been considered as some of the most promising targets for antibiotics development in pathogenic species. In this study, a three-dimensional structural model of Brucella abortus threonyl-tRNA synthetase (BaThrRS) was constructed using computer-aided molecular modeling technique taking Escherichia coli threonyl-tRNA synthetase (EThrRS, PDB ID: 1QF6) as template. The ZINC natural product database including 11247 compounds was subjected for virtual screening based on molecular docking against the ATP binding site of the target using Autodock Vina program. Considering the mode of binding and affinities, seven leads, ZINC67910544 (–12.4 kcal/mol), ZINC72320615 (–12.3 kcal/mol), ZINC72320626 (–12.2 kcal/mol), ZINC27215482 (–12.6 kcal/mol), ZINC35270978 (–12.1 kcal/mol), ZINC35458951 (–12.1 kcal/mol), and ZINC42805205 (–12.4 kcal/mol) were selected on basis of binding energies in comparison to the selective inhibitor borrelidin (free energy of binding: –9.3 kcal/mol). Among them, ZINC27215482 (–12.6 kcal/mol) was best lead because of its highest inhibitory activity. The binding site of ZINC27215482 on BaThrRS was a pocket consisting of 22 residues: TYR316, ASN319, MET341, ASN342, CYS343, GLN374, MET383, ARG384, VAL385, PHE388, GLN390, ASP392, HIS394, TYR476, LYS479, GLN493, GLN498, THR496, GLN498, HIS525, SER531, and ARG534. Therefore, through a high throughput virtual screen we identified seven novel BaThrRS inhibitors that are used against bovine brucellosis with great potential for further development.

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