微分子对接、DFT分析和ADMET研究了香豆根中咔唑类生物碱和香豆素:一个有效的群体感应抑制剂。

Q2 Biochemistry, Genetics and Molecular Biology
Advances and Applications in Bioinformatics and Chemistry Pub Date : 2021-02-05 eCollection Date: 2021-01-01 DOI:10.2147/AABC.S290912
Rajalakshmanan Eswaramoorthy, Hadgu Hailekiros, Fedlu Kedir, Milkyas Endale
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引用次数: 21

摘要

在现代药物设计中,计算机方法被广泛用于理解药物受体相互作用和量子化学性质。本研究采用计算从头设计的方法确定了从芫花根中分离的咔唑生物碱(1)和三种香豆素(2-4)的抗菌活性结合模式,阐明了它们的量子化学性质和admet -药物相似性。方法:采用AutoDock Vina柔性配体对接方法,对DNA-Gyrase (6F86)和LasR结合域(2UV0)进行对接研究。通过ADMET进行SwissADME预测和毒理学预测。采用B3LYP/6-31G基水平DFT分析,预测了优化后化合物的结构和分子静电势面。结果与讨论:对接结果显示,化合物3对DNA回转酶B和LasR结合域的对接得分均优于环丙沙星,具有作为细菌DNA回转酶和群体感应LasR结合域抑制剂的潜力。SwissADME预测结果表明,分离得到的化合物(1-4)均满足Lipinski的5个规则,零违逆。毒理学预测结果表明,所有化合物和环丙沙星均无肝毒性、无致癌性、无刺激性、免疫原性和无细胞毒性。DFT分析结果表明,化合物3具有较大的电负性(χeV)、全局柔软性(σ eV-1)、全局亲电性(ωeV),致突变性值接近环丙沙星(LD50值为480 mg/kg),具有较好的生物活性和化学反应性,电子给体到电子受体基团之间的分子内电荷转移较大。结论:综上所述,化合物3可作为先导分子开发成大肠杆菌DNA旋切酶B抑制剂和铜绿假单胞菌群体感应自诱导剂LasR结合域的有效抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

In silico Molecular Docking, DFT Analysis and ADMET Studies of Carbazole Alkaloid and Coumarins from Roots of <i>Clausena anisata</i>: A Potent Inhibitor for Quorum Sensing.

In silico Molecular Docking, DFT Analysis and ADMET Studies of Carbazole Alkaloid and Coumarins from Roots of <i>Clausena anisata</i>: A Potent Inhibitor for Quorum Sensing.

In silico Molecular Docking, DFT Analysis and ADMET Studies of Carbazole Alkaloid and Coumarins from Roots of <i>Clausena anisata</i>: A Potent Inhibitor for Quorum Sensing.

In silico Molecular Docking, DFT Analysis and ADMET Studies of Carbazole Alkaloid and Coumarins from Roots of Clausena anisata: A Potent Inhibitor for Quorum Sensing.

Introduction: In modern drug design, in silico methods are largely used to understand drug-receptor interactions and quantum chemical properties. In the present study, a computational de novo design approach was used to confirm mode of binding for antibacterial activity, elucidating quantum chemical properties and ADMET-drug-likeness of carbazole alkaloid (1) and three coumarins (2-4) isolated from roots of Clausena anisata.

Methods: Docking studies were performed with DNA-Gyrase (6F86) and LasR binding domain (2UV0) employing a flexible ligand docking approach using AutoDock Vina. SwissADME prediction and toxicological predictions were performed by ADMET. The optimized structures and molecular electrostatic potential surface of the isolated compounds were predicted by DFT analysis using B3LYP/6-31G basis levels.

Results and discussion: The docking results revealed that compound 3 showed better docking scores against both DNA gyrase B and LasR binding domain compared with ciprofloxacin with potential as an inhibitor of bacterial DNA gyrase and quorum sensing LasR binding domain. The SwissADME prediction results showed that all the isolated compounds (1-4) satisfy Lipinski's rule of five with zero violations. Toxicological prediction results suggested that all compounds and ciprofloxacin are non-hepatotoxic, non-carcinogenic, non-irritant, immunogenic, and non-cytotoxic. The DFT analysis results revealed that compound 3 has large electronegativity (χeV), global softness (σ eV-1), global electrophilicity (ωeV), and mutagenicity value closer to ciprofloxacin (with LD50 value of 480 mg/kg) suggesting better bioactivity and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups.

Conclusion: Overall, compound 3 may serve as a lead molecule that could be developed into a potent E. coli DNA gyrase B inhibitor and efficient inhibitor for quorum sensing auto-inducer LasR binding domain of Pseudomonas aeruginosa.

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来源期刊
Advances and Applications in Bioinformatics and Chemistry
Advances and Applications in Bioinformatics and Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
6.50
自引率
0.00%
发文量
7
审稿时长
16 weeks
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