College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou, China.
Department of Chemistry, Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA.
J Enzyme Inhib Med Chem. 2024 Dec;39(1):2387415. doi: 10.1080/14756366.2024.2387415. Epub 2024 Aug 14.
EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that (IC = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC = 45.8 μM). Additionally, the inhibitory kinetic study indicated that (K = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the -position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.
ECGUS 作为减轻严重 GIAEs 的靶点引起了相当多的关注。在这项研究中，设计、合成并进行了一系列 72 种（硫）脲衍生物的生物测定。生物测定结果表明，化合物 （IC = 2.68 μM）对 EcGUS 表现出有希望的抑制作用，超过了 EcGUS 抑制剂 D-山梨糖醇-1,4-内酯（DSL，IC = 45.8 μM）。此外，抑制动力学研究表明，化合物 （K = 1.64 μM）对 EcGUS 表现为非竞争性抑制剂。构效关系研究表明，在苯环的 -位引入吸电子基团有利于提高对 EcGUS 的抑制活性。此外，分子对接分析表明，化合物 通过与残基 Asp 163、Tyr 472 和 Glu 504 形成相互作用，对 EcGUS 具有很强的亲和力。总的来说，这些结果表明化合物 可能是一种有效的 EcGUS 抑制剂，为开发针对 EcGUS 的新型抑制剂提供了有价值的见解和指导。
