Kovalenko Oksana P, Volynets Galyna P, Rybak Mariia Yu, Starosyla Sergiy A, Gudzera Olga I, Lukashov Sergiy S, Bdzhola Volodymyr G, Yarmoluk Sergiy M, Boshoff Helena I, Tukalo Michael A
Department of Protein Synthesis Enzymology , Institute of Molecular Biology and Genetics , The NAS of Ukraine , 150 Zabolotnogo St , 03143 Kyiv , Ukraine . Email:
Department of Medicinal Chemistry , Institute of Molecular Biology and Genetics , The NAS of Ukraine , 150 Zabolotnogo St , 03143 Kyiv , Ukraine.
Medchemcomm. 2019 Nov 28;10(12):2161-2169. doi: 10.1039/c9md00347a. eCollection 2019 Dec 1.
Effective treatment of tuberculosis is challenged by the rapid development of () multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, -benzylidene-'-thiazol-2-yl-hydrazines. Molecular docking of a library of novel -benzylidene-'-thiazol-2-yl-hydrazine derivatives into active sites of LeuRS (LeuRS) and MetRS (MetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against LeuRS and 28 compounds active against MetRS. The hit compounds display dual inhibitory potency as demonstrated by IC values for both enzymes. Compound is active against H37Rv cells in bioassays.
结核病的有效治疗面临着多药耐药性迅速发展的挑战，而新型多靶点药物可能克服这一问题。氨酰-tRNA合成酶（AARSs）是蛋白质生物合成机制的重要组成部分，也是药物研发的有吸引力的靶点。在此，我们通过实验验证了单一抑制剂同时靶向结构相关AARSs的假设。我们之前鉴定出一类新的分枝杆菌亮氨酰-tRNA合成酶抑制剂，即α-亚苄基-β-噻唑-2-基肼。将一系列新型α-亚苄基-β-噻唑-2-基肼衍生物分子对接至亮氨酰-tRNA合成酶（LeuRS）和甲硫氨酰-tRNA合成酶（MetRS）的活性位点，得到了一组排名靠前的化合物，随后对其酶活性进行了评估。筛选数据显示，有11种化合物对LeuRS有活性，28种化合物对MetRS有活性。命中的化合物表现出双重抑制活性，这通过两种酶的IC值得到证明。化合物在生物测定中对H37Rv细胞有活性。
