College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha W. University, Seoul, Republic of Korea.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):776-784. doi: 10.1080/14756366.2021.1900166.
d--β-d--heptose-1-phosphate adenylyltransferase from (HldC) is the fourth enzyme in the ADP-l--β-d--heptose biosynthesis pathway producing a lipopolysaccharide core. Therefore, HldC is an anti-melioidosis target. Three ChemBridge compounds purchased from ChemBridge Corporation (San Diego, CA) were found to have an effective inhibitory activity on HldC. Interestingly, ChemBridge 7929959 was the most effective compound due to the presence of the terminal benzyl group. The enzyme kinetic study revealed that most of them show mixed type inhibitory modes against ATP and βG1P. The induced-fit docking indicated that the medium affinity of ChemBridge 7929959 is originated from its benzyl group occupying the substrate-binding pocket of HldC. The inhibitory role of terminal aromatic groups was proven with ChemBridge 7570508. Combined with the previous study, ChemBridge 7929959 is found to work as a dual inhibitor against both HldC and HddC. Therefore, three ChemBridge compounds can be developed as a potent anti-melioidosis agent with a novel inhibitory concept.
从（HldC）中分离得到 d--β-d--庚糖-1-磷酸腺苷酰转移酶，是 ADP-l--β-d--庚糖生物合成途径中的第四种酶，可产生脂多糖核心。因此，HldC 是抗类鼻疽的靶点。从 ChemBridge 公司（加利福尼亚州圣地亚哥）购买的三种 ChemBridge 化合物被发现对 HldC 具有有效的抑制活性。有趣的是，由于存在末端苄基，ChemBridge 7929959 是最有效的化合物。酶动力学研究表明，它们中的大多数对 ATP 和βG1P 表现出混合抑制模式。诱导契合对接表明，ChemBridge 7929959 的中等亲和力源于其苄基占据了 HldC 的底物结合口袋。末端芳香基团的抑制作用已被 ChemBridge 7570508 证实。结合以前的研究，发现 ChemBridge 7929959 可作为 HldC 和 HddC 的双重抑制剂。因此，三种 ChemBridge 化合物可以作为一种具有新型抑制概念的潜在抗类鼻疽药物进行开发。
