Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/Lipophilic Phosphonate Complexes
Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/Lipophilic Phosphonate Complexes
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DOI：
10.1021/ml100243r
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Song, Yongcheng
中科院分区：
文献类型：
--
作者：
Deng, Lisheng;Endo, Kiwamu;Song, Yongcheng
磷霉素是一种有效的1-脱氧-D-木酮糖-5-磷酸还原异构酶（DXR）抑制剂，具有抗菌和抗疟活性。由于其不良的药代动力学，需要更多的亲脂性DXR抑制剂。然而，DXR中的疏水结合位点仍然难以捉摸。在此，含有吡啶/喹啉的膦酸盐被鉴定为DXR抑制剂，IC 50值低至840 nM。我们还报告了三种DXR/抑制剂结构，揭示了一种新型结合模式。发现Trp 211的吲哚基团移动类似于4.6埃以打开主要疏水的口袋，其中抑制剂的吡啶/喹啉环位于与吲哚具有强的pi=pi堆积/电荷转移相互作用的地方。对接研究表明，我们的结构可以用来预测其他亲脂性DXR抑制剂的结合模式。总之，这项工作显示了Trp 211在抑制剂识别中的重要作用，并为未来的药物设计和开发提供了结构基础。
Fosmidomycin, a potent inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase-(DXR), has-antibacterial and antimalaria activity. Due to its poor pharmacokinetics, more lipohilic DXR inhibitors are needed. However, the hydrophobic binding site(s) in DXR remains elusive. Here, pyridine/quinoline containing phosphonates are identified to be DXR in inhibitor with IC50 values as low as 840 nM. We also report three DXR/inhibitor structures, revealing a novel binding mode. The indole group of Trp211 is found to move similar to 4.6 angstrom to open up a mainly hydrophobic pocket, where the pyridine/quinoline rings of the inhibitors are located an have strong pi=pi stacking/charge-transfer interactions with the indole. Docking studies demonstrate our structures could be used to predict the binding modes of other liphophilic DXR inhibitors. Overall, this work shows an important role of Trp211 in inhibitor recognition and provides a structural basis for future drug design and development.