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首页> 外文期刊>Chemistry: A European journal >Freezing the Dynamic Gap for Selectivity: Motion-Based Design of Inhibitors of the Shikimate Kinase Enzyme
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Freezing the Dynamic Gap for Selectivity: Motion-Based Design of Inhibitors of the Shikimate Kinase Enzyme

机译：冻结选择性的动态差距：Shikimate激酶抑制剂的基于运动的设计。

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Shikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5-aminoshikimic acid and the natural substrate enhances the selectivity for the H. pylori enzyme due to key motion differences in the shikimic acid binding domain (mainly helix alpha 5). These studies show that the less-exploited motion-based design approach not only is an alternative strategy for the development of competitive inhibitors, but could also be a way to achieve selectivity against a particular enzyme among its homologues.
机译：Shikimate激酶（SK）是芳香族氨基酸生物合成的第五种酶，是公认的抗生素药物开发目标。通过分子动力学模拟观察发现了独特的动态非极性间隙的潜力，该间隙将天然底物与溶剂环境隔离开来进行催化，并且通过分子动力学模拟观察到了结核分枝杆菌和幽门螺杆菌SK酶的运动。生化和计算研究的结果表明，由于sh草酸结合域（主要是螺旋结构）中的关键运动差异，在5-氨基ki草酸的C5位和天然底物上引入大基团可增强对幽门螺杆菌的选择性。 alpha 5）。这些研究表明，利用较少的基于运动的设计方法不仅是开发竞争性抑制剂的替代策略，而且还可能是针对其同系物中的特定酶实现选择性的一种方法。

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