四氮散治疗焦虑性失眠的多靶点机制:网络药理学和分子对接分析实例。

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chih Ting Lin, Hsin Yi Lin, Wen Huang Peng, Lung Yuan Wu
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引用次数: 0

摘要

背景和目的:基于网络药理学和分子对接分析,本研究旨在揭示四氮散(SNS)治疗焦虑性失眠的多重机制:方法:对 "四逆散 "的化合物进行了细致的分析、筛选和标准化,并参考了其药理属性。这些成分包括柴胡、白芍、枳壳和甘草。我们利用中药系统药理学数据库(TCMSP)、中药综合数据库(TCMID)、GeneCards数据库、治疗靶点数据库(TTD)和比较毒物基因组学数据库(CTD)构建了成分-化合物-靶点网络,并使用Cytoscape 3.9.1软件对结果进行了可视化。随后,利用 STRING 数据库和 Cytoscape 3.9.1 软件构建了蛋白质-蛋白质相互作用(PPI)网络,并将其可视化。此外,还通过注释、可视化和综合发现数据库(DAVID)进行了基因本体(GO)和京都基因组百科全书(KEGG)通路富集分析。使用 AutoDock 4.2 软件进行了分子对接程序,以了解目标受体与所选化合物配体之间的相互作用:我们对 SNS 中的 31 种药理活性化合物进行了彻底分类和筛选。结果:我们对 SNS 中的 31 种药理活性化合物进行了彻底的分类和筛选,随后预测出了几个潜在的靶基因,其中有 59 个靶基因与焦虑性失眠明显相关。PPI分析表明,核心靶蛋白包括AKT1、IL6、TNF、SLC6A4、MAOA和GABRA2。我们的研究结果表明,SNS 可通过减少炎症、神经变性和神经元细胞凋亡来缓解焦虑性失眠。此外,GO 和 KEGG 富集分析结果表明,SNS 可通过与神经活性配体-受体相互作用途径相关的机制调节焦虑性失眠症的多个方面。这些途径包括各种突触传递途径以及与反应途径相关的抗炎活性。在比较 "成分-化合物-靶标 "网络和 "化合物-靶标-突触通路 "网络时,我们选择了β-谷甾醇、堪非醇、四甲氧基木犀草素、异鼠李素和辛柚素等五个活性化合物进行分子对接实验。在分子对接实验中,选择了 11 个靶蛋白(AKT1、SLC6A4、ADRB2、MAOA、ACHE、ESR1、CYP3A4、CHRNA7、GABRA2、HTR2A 和 NOS3)作为受体,它们在 PPI 网络中对 5-羟色胺能、胆碱能、多巴胺能和 GABA 能系统也起着重要的调节作用。结果表明,异鼠李素-AKT1、异鼠李素-SLC6A4、β-谷甾醇-MAOA、β-谷甾醇-ACE、异鼠李素-CHRNA7和shinpterocarpin-GABRA2等对接配对提供了关键化合物与SNS核心靶蛋白之间配体-受体结合的最稳定构象:本研究提供了一个计算结果,揭示了SNS可通过 "多化合物、多靶点和多途径 "机制缓解与焦虑相关的睡眠障碍。网络药理学和分子对接结果从理论上证实了 SNS 的抗焦虑和抗失眠作用。虽然这项研究纯粹是统计性和系统性的,没有经过经验验证,但它可以作为后续实验研究的垫脚石和基石。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Multi-Target Mechanisms of Si-Ni-San on Anxious Insomnia: An Example of Network-pharmacology and Molecular Docking Analysis.

Background and objective: Based on comprehensive network-pharmacology and molecular docking analysis, this study was intended to unveil the multiple mechanisms of Si-Ni-San (SNS) in treating anxious insomnia.

Methods: The compounds of SNS were meticulously analyzed, selected and standardized with references to their pharmacological attributes. The components included chaihu (Bupleurum chinense DC.), baishao (Paeonia lactiflora Pall.), zhishi (Citrus aurantium L.) and gancao (Glycyrrhiza uralensis Fisch. ex DC.). We used the Traditional Chinese Medicine System Pharmacology (TCMSP) Database, Traditional Chinese Medicines Integrated Database (TCMID), GeneCards database, therapeutic target database (TTD) and comparative toxicogenomic database (CTD) to construct the components-compounds-targets networks and used Cytoscape 3.9.1 software to visualize the outcome. Afterwards, the STRING database and Cytoscape 3.9.1 software were utilized to construct and visualize the protein-protein interaction (PPI) network analysis. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The molecular docking program was carried out using AutoDock 4.2 software to understand interactions between target receptors and compound ligands selected for study.

Results: We thoroughly sorted and filtered 31 pharmacologically active compounds from SNS. Subsequently, several potential target genes were predicted, of which there were 59 target genes distinctly associated with anxious insomnia. The PPI analysis indicated that the core target proteins included AKT1, IL6, TNF, SLC6A4, MAOA and GABRA2. The results of our study indicated that SNS potentially remediates anxious insomnia by reducing inflammation, neurodegeneration, and cell apoptosis of neurons. In addition, GO and KEGG enrichment analysis results indicated that SNS could modulate multiple aspects of anxious insomnia through mechanisms related to pathways of neuroactive ligand-receptor interaction. These pathways include various kinds of synaptic transmission pathways, and anti-inflammatory activity associated with response pathways. When we compared the components-compounds-targets networks and the compounds-targets-synaptic pathways networks, the five active compounds, including beta-Sitosterol, Kaempferol, Tetramethoxyluteolin, Isorhamnetin and Shinpterocarpin, were selected to conduct molecular docking experiments. Eleven target proteins, (AKT1, SLC6A4, ADRB2, MAOA, ACHE, ESR1, CYP3A4, CHRNA7, GABRA2, HTR2A and NOS3), which also play significant roles in regulating serotonergic, cholinergic, dopaminergic and GABAergic systems in the PPI network, were selected to act as receptors in molecular docking trials. The results showed that docking pairs isorhamnetin-AKT1, isorhamnetin-SLC6A4, β-sitosterol-MAOA, β- sitosterol-ACHE, isorhamnetin-CHRNA7 and shinpterocarpin-GABRA2 provided the most stable conformations of ligand-receptor binding between key compounds and core target proteins in the SNS.

Conclusion: In the study, we offer a computational result, revealing that SNS may alleviate sleep disorders associated with anxiety through a "multi-compounds, multi-targets, and multi-pathways" mechanism. The network-pharmacology and molecular docking outcomes could theoretically confirm the anti-anxiety and anti-insomnia effects of SNS. Although this research is purely statistical and systematic without empirical validation, it serves as a stepping stone and cornerstone for subsequent experimental investigations.

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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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