紫杉叶素作为结核分枝杆菌DNA回旋酶和异亮氨酰-tRNA合成酶的双重抑制剂：计算机模拟分子对接、动力学模拟及体外实验
Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays.
作者信息
Kozhikkadan Davis Charles, Nasla K, Anjana A K, Rajanikant G K
机构信息
1School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601 India.
Department of Pharmacognosy and Phytochemistry, Jamia Salafiya Pharmacy College, Malappuram, 673637 India.
出版信息
In Silico Pharmacol. 2018 Apr 9;6(1):8. doi: 10.1007/s40203-018-0045-5. eCollection 2018.
DNA gyrase and aminoacyl-tRNA synthetases are two essential bacterial enzymes involved in DNA replication, transcription and translation. Flavonoids are plant secondary metabolites with variable phenolic structures. In this study, eight flavonoids structurally similar to quercetin were selected and their ADMET properties were evaluated. Molecular docking and free energy calculations were carried out to examine the binding of these flavonoids to the ATP-binding site and editing domain of DNA gyrase and Isoleucyl-tRNA synthetase, respectively. Taxifolin was found out to be the top lead molecule in both the docking studies with a good number of interactions with the active site amino acids. Further, binding of taxifolin to the proteins was extensively studied using 50 ns molecular dynamics simulation. In vitro anti-tuberculosis activity of taxifolin was evaluated and compared with the standard drugs. Minimal inhibition concentration of taxifolin was found to be ≤ 12.5 μg/ml.
DNA 回旋酶和氨酰 - tRNA 合成酶是参与 DNA 复制、转录和翻译的两种重要细菌酶。类黄酮是具有可变酚类结构的植物次生代谢产物。在本研究中，选择了八种结构与槲皮素相似的类黄酮，并评估了它们的 ADMET 性质。分别进行了分子对接和自由能计算，以研究这些类黄酮与 DNA 回旋酶的 ATP 结合位点和异亮氨酰 - tRNA 合成酶的编辑结构域的结合情况。在两项对接研究中均发现水飞蓟宾是最佳先导分子，它与活性位点氨基酸有大量相互作用。此外，使用 50 纳秒分子动力学模拟广泛研究了水飞蓟宾与蛋白质的结合。评估了水飞蓟宾的体外抗结核活性，并与标准药物进行了比较。发现水飞蓟宾的最低抑菌浓度≤12.5μg/ml。
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