Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
Molecules. 2019 Oct 18;24(20):3756. doi: 10.3390/molecules24203756.
A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from (DsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to DsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of DsbA. Binding affinity was calculated based on NMR studies and compounds and were identified as the highest affinity binders with dissociation constants () of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of DsbA inhibitors.
采用基于片段的药物发现方法来针对 （DsbA）中的硫醇-二硫键氧化还原酶 DsbA。该酶对于许多致病性革兰氏阴性细菌中毒力因子的正确折叠至关重要，小分子抑制剂有可能被开发为抗毒力化合物。对片段文库的生物物理筛选鉴定出了几类与 DsbA 具有亲和力的片段。一个具有高 mM 亲和力的命中物，2-(6-溴苯并呋喃-3-基)乙酸（），在支架的几个位置进行了化学修饰。修饰类似物的 X 射线晶体结构显示与 DsbA 的催化二硫键相邻的疏水性结合槽结合。根据 NMR 研究计算了结合亲和力，化合物 和 被鉴定为具有最高亲和力的配体，解离常数（）分别为 326 ± 25 和 341 ± 57 µM。这项工作表明有可能将苯并呋喃片段开发成一类新型的 DsbA 抑制剂。
