-亮氨酰苯磺酰胺作为结构简化的亮氨酰-tRNA合成酶抑制剂。
-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors.
作者信息
Charlton Michael H, Aleksis Rihards, Saint-Leger Adélaïde, Gupta Arya, Loza Einars, Ribas de Pouplana Lluís, Kaula Ilze, Gustina Daina, Madre Marina, Lola Daina, Jaudzems Kristaps, Edmund Grace, Randall Christopher P, Kime Louise, O'Neill Alex J, Goessens Wil, Jirgensons Aigars, Finn Paul W
机构信息
Oxford Drug Design Ltd., Oxford Centre for Innovation, New Road, Oxford, OX1 1BY. U.K.
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
出版信息
ACS Med Chem Lett. 2018 Jan 18;9(2):84-88. doi: 10.1021/acsmedchemlett.7b00374. eCollection 2018 Feb 8.
-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure-activity relationship analysis. Enzymatic assays revealed that -leucinyl benzenesulfonamides display remarkable selectivity for leucyl-tRNA synthetase compared to and human orthologues. The simplest analogue of the series, -leucinyl benzenesulfonamide (R = H), showed the highest affinity against leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, ATCC 25922), which renders it as a promising template for antibacterial drug discovery.
亮氨酰苯磺酰胺已被发现是一类新型的亮氨酰 - tRNA合成酶强效抑制剂。通过等温滴定量热法测定抑制剂与该酶的结合情况。这提供了有关结合过程中焓和熵贡献的信息，这些信息与对接研究一起用于构效关系分析。酶活性测定表明，与大肠杆菌和人类同源物相比，亮氨酰苯磺酰胺对亮氨酰 - tRNA合成酶具有显著的选择性。该系列中最简单的类似物，亮氨酰苯磺酰胺（R = H），对亮氨酰 - tRNA合成酶表现出最高的亲和力，并且对革兰氏阴性病原体也具有抗菌活性（最佳最低抑菌浓度 = 8 μg/mL，大肠杆菌ATCC 25922），这使其成为抗菌药物发现的一个有前景的模板。
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