Structure-based inhibitor discovery of Helicobacter pylori dehydroquinate synthase
Structure-based inhibitor discovery of Helicobacter pylori dehydroquinate synthase
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DOI：
10.1016/j.bbrc.2008.05.070
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发表时间：
2008-08-15
影响因子：
3.1
通讯作者：
Wang, Wen-Ching
中科院分区：
文献类型：
--
作者：
Liu, Jai-Shin;Cheng, Wen-Chi;Wang, Wen-Ching
脱氢奎宁酸合成酶 (DHQS) 是一种烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性酶，可将 3-脱氧-D-阿拉伯-庚酮酸 7-磷酸 (DAHP) 转化为 3-脱氢奎宁酸 (DHQ)。由于它催化莽草酸途径中的第二个关键步骤，这对于细菌、真菌和植物中的芳香族氨基酸代谢至关重要，但在哺乳动物中则不然，因此 DHQS 是新型抗菌剂、抗寄生虫剂和除草剂的潜在目标。幽门螺杆菌 DHQS (HpDHQS) 与 NAD 复合物的晶体结构已在 2.4 埃分辨率下测定，并发现其具有 N 端罗斯曼折叠结构域和 C 端 α 螺旋结构域。结构比较表明，二元复合物采用开放态构象，并在结合口袋中共享保守残基。使用 GOLD 对接程序将化合物虚拟对接至 HpDHQS 结构的活性位点，从而鉴定出多种抑制剂。最活跃的化合物的 IC50 值为 61 μM，可以作为有效抑制剂的先导物。 (C) 2008 Elsevier Inc. 保留所有权利。
Dehydroquinate synthase (DHQS) is a nicotinamide adenine dinucleotide (NAD)-dependent enzyme that converts 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) into 3-dehydroquinate (DHQ). Since it catalyzes the second key step in the shikimate pathway, which is crucial for the aromatic amino acid metabolism in bacteria, fungi, and plants, but not in mammals, DHQS is a potential target for new antimicrobial agents, anti-parasitic agents and herbicides. The crystal structure of Helicobacter pylori DHQS (HpDHQS) complexed with NAD has been determined at 2.4-angstrom resolution and was found to possess an N-terminal Rossmann-fold domain and a C-terminal alpha-helical domain. Structural comparison reveals that the binary complex adopts an open-state conformation and shares conserved residues in the binding pocket. Virtual docking of compounds into the active site of the HpDHQS structure using the GOLD docking program led to the identification of several inhibitors. The most active compound had an IC50 value of 61 mu M, which may serve as a lead for potent inhibitors. (C) 2008 Elsevier Inc. All rights reserved.