Mycobacterium tuberculosis infection remains a major cause of global morbidity and mortality due to the increase of antibiotics resistance. Dual/multi-target drug discovery is a promising approach to overcome bacterial resistance. In this study, we built ligand-based pharmacophore models and performed pharmacophore screening in order to identify hit compounds targeting simultaneously two enzymes-M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). In vitro aminoacylation assay revealed five compounds from different chemical classes inhibiting both enzymes. Among them 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 (1) inhibits mycobacterial LeuRS and MetRS with IC50 values of 13 µM and 13.8 µM, respectively. Molecular modeling study indicated that compound 1 has similar binding mode with the active sites of both aminoacyl-tRNA synthetases and can be valuable compound for further chemical optimization in order to find promising antituberculosis agents.

中文翻译：

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使用药效团筛选进行双目标命中鉴定。

由于抗生素耐药性的增加，结核分枝杆菌感染仍然是全球发病率和死亡率的主要原因。双/多靶点药物发现是克服细菌耐药性的一种有前途的方法。在这项研究中，我们建立了基于配体的药效团模型并进行了药效团筛选，以鉴定同时靶向两种酶M的命中化合物。结核病的亮氨酰tRNA合成酶（LeuRS）和甲硫氨酰tRNA合成酶（MetRS）。体外氨基酰化测定揭示了来自不同化学类别的五种化合物抑制两种酶。其中最具活性的化合物-3-（3-氯-4-甲氧基-苯基）-5- [3-（4-氟-苯基）-[1,2,4]恶二唑-5-基] -3H- [1,2,3]三唑-4-基胺（1）抑制分枝杆菌LeuRS和MetRS的IC50值分别为13 µM和13.8 µM。