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Elaboration of a benzofuran scaffold and evaluation of binding affinity and inhibition of Escherichia coli DsbA: A fragment-based drug design approach to novel antivirulence compounds
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2021-07-22 , DOI: 10.1016/j.bmc.2021.116315
Luke F Duncan 1 , Geqing Wang 2 , Olga V Ilyichova 3 , Rabeb Dhouib 4 , Makrina Totsika 4 , Martin J Scanlon 5 , Begoña Heras 2 , Belinda M Abbott 1
Affiliation  

Bacterial thiol-disulfide oxidoreductase DsbA is essential for bacterial virulence factor assembly and has been identified as a viable antivirulence target. Herein, we report a structure-based elaboration of a benzofuran hit that bound to the active site groove of Escherichia coli DsbA. Substituted phenyl groups were installed at the 5- and 6-position of the benzofuran using Suzuki-Miyaura coupling. HSQC NMR titration experiments showed dissociation constants of this series in the high µM to low mM range and X-ray crystallography produced three co-structures, showing binding in the hydrophobic groove, comparable with that of the previously reported benzofurans. The 6-(m-methoxy)phenyl analogue (2b), which showed a promising binding pose, was chosen for elaboration from the C-2 position. The 2,6-disubstituted analogues bound to the hydrophobic region of the binding groove and the C-2 groups extended into the more polar, previously un-probed, region of the binding groove. Biochemical analysis of the 2,6-disubsituted analogues showed they inhibited DsbA oxidation activity in vitro. The results indicate the potential to develop the elaborated benzofuran series into a novel class of antivirulence compounds.



中文翻译:

苯并呋喃支架的制作以及对大肠杆菌 DsbA 的结合亲和力和抑制作用的评估:一种基于片段的新型抗毒化合物药物设计方法

细菌硫醇二硫化物氧化还原酶 DsbA 对细菌毒力因子组装至关重要,已被确定为可行的抗毒力靶标。在此,我们报告了基于结构的苯并呋喃命中,该命中绑定到大肠杆菌DsbA的活性位点凹槽。使用 Suzuki-Miyaura 偶联将取代的苯基安装在苯并呋喃的 5 位和 6 位。HSQC NMR 滴定实验表明,该系列的解离常数在高 µM 至低 mM 范围内,X 射线晶体学产生了三个共结构,显示在疏水凹槽中的结合,与之前报道的苯并呋喃相当。6-(-甲氧基)苯基类似物(2B),显示出有希望的绑定姿势,被选择从 C-2 位置进行详细说明。2,6-二取代的类似物与结合沟的疏水区结合,C-2 基团延伸到结合沟的极性更强、以前未探测过的区域。2,6-二取代类似物的生化分析表明它们在体外抑制了 DsbA 氧化活性。结果表明将精细的苯并呋喃系列开发成一类新型抗毒化合物的潜力。

更新日期:2021-08-05
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