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[摘要]：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. |
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