Biomolecular Interaction Centre and Department of Chemistry, University of Canterbury, Christchurch 8140, New Zealand.
Bioorg Med Chem Lett. 2011 Sep 1;21(17):5092-7. doi: 10.1016/j.bmcl.2011.03.071. Epub 2011 Apr 12.
3-Deoxy-d-arabino-heptulosonate 7-phosphate (DAH7P) synthase catalyses the first step of the shikimate pathway for the biosynthesis of aromatic compounds. Enzymes of this pathway have been identified as potential targets for drug design. The reaction catalysed by DAH7P synthase is an aldol condensation between phosphoenolpyruvate (PEP) and d-erythrose 4-phosphate (E4P). In this study inhibitors of DAH7P synthase were prepared which were designed to fit into the binding sites of both PEP and E4P substrates simultaneously. Inhibitors, known to target the PEP binding site, were extended using a C4 linker to include an appropriately placed phosphate group in order to access the phosphate-binding site of E4P. A small increase in inhibition was observed with this modification, and the inhibition results have been rationalised by induced-fit docking.
3-脱氧-D-阿拉伯庚酮糖-7-磷酸（DAH7P）合酶催化芳香族化合物生物合成的莽草酸途径的第一步。该途径的酶已被确定为药物设计的潜在靶标。DAH7P 合酶催化的反应是磷酸烯醇丙酮酸（PEP）和 D-赤藓糖 4-磷酸（E4P）之间的醛缩合。在这项研究中，制备了 DAH7P 合酶的抑制剂，这些抑制剂被设计成同时适合 PEP 和 E4P 底物的结合位点。已知针对 PEP 结合位点的抑制剂通过 C4 接头进行了扩展，其中包含一个适当放置的磷酸基团，以便进入 E4P 的磷酸结合位点。通过这种修饰观察到抑制作用略有增加，并且通过诱导契合对接对抑制结果进行了合理化。
