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首页> 外文期刊>Journal of Bioinformatics and Computational Biology >Systematic analysis and integrative discovery of active-site subpocket-specific dehydroquinate synthase inhibitors combating antibiotic-resistant Staphylococcus aureus infection
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Systematic analysis and integrative discovery of active-site subpocket-specific dehydroquinate synthase inhibitors combating antibiotic-resistant Staphylococcus aureus infection

机译：抗抗生素抗性金黄色葡萄球菌感染的系统分析和综合发现对抗抗生素抗性葡萄球菌感染的系统分析和综合发现

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摘要

Shikimate pathway plays an essential role in the biosynthesis of aromatic amino acids in various plants and bacteria, which consists of seven key enzymes and they are all attractive targets for antibacterial agent development due to their absence in humans. The Staphylococcus aureus dehydroquinate synthase (SaDHQS) is involved in the second step of shikimate pathway, which catalyzes the NAD(+)-dependent conversion of 3-deoxy-D-arabino-heptulosonate-7-phosphate to dehydroquinate via multiple steps. The enzyme active site can be characterized by two spatially separated subpockets 1 and 2, which represent the reaction center of substrate adduct with NAD(+) nicotinamide moiety and the assistant binding site of NAD thorn adenine moiety, respectively. In silico virtual screening is performed against a biogenic compound library to discover SaDHQS subpocket-specific inhibitors, which were then tested against both antibiotic-sensitive and antibiotic-resistant S. aureus strains by using in vitro susceptibility test. The activity profile of hit compounds has no considerable difference between the antibiotic-sensitive and -resistant strains. The subpocket 1-specific inhibitors exhibit a generally higher activity than subpocket 2-specific inhibitors, and they also hold a strong selectivity between their cognate and noncognate subpockets. Dynamics and energetics analyses reveal that the SaDHQS active site prefers to interact with amphipathic and polar inhibitors by forming multiple hydrogen bonds and van der Waals packing at the complex interfaces of the two subpockets with their cognate inhibitors.
机译：Shikimate途径在各种植物和细菌中的芳族氨基酸的生物合成中起重要作用，该细菌由七个关键酶组成，它们是由于它们在人类中缺失而导致的抗菌剂发育的所有靶标。金黄色葡萄球菌脱氢含量合成酶（Sadhqs）涉及Shikimate途径的第二步，其催化NAD（+） - 依赖于3-脱氧-D-Arabino-庚烷醇酯-7-磷酸酯的转化率通过多个步骤脱卤化。酶活性位点可以通过两个空间分离的子谱图1和2来表征，其代表与NAD（+）烟酰胺部分和NAD刺腺嘌呤部分的助剂结合位点的底物加合物的反应中心。在硅的虚拟筛选中，对生物化合物库进行，以发现Sadhqs诱导特异性抑制剂，然后通过使用体外敏感性试验对抗生素敏感和抗生素抗性的金黄色葡萄球菌进行测试。抗生素敏感菌株与抗生素敏感菌株之间的活性概况没有相当大的差异。子壳体1特异性抑制剂的活性通常高于细胞插座2特异性抑制剂，并且它们在其同源和非认知子页面之间存在强烈的选择性。动态和能量分析表明，Sadhqs活性位点通过在具有其同源抑制剂的两个子载体的复杂界面处形成多个氢键和范德瓦尔斯包装来与两性和极性抑制剂相互作用。

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