Mechanism of Relieving Alcohol and Protecting Liver of Yigancao Herbal Tea Based on Network Pharmacology and Molecular Docking Technology
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摘要: 目的：通过网络药理学方法和分子对接技术，探讨益肝草凉茶解酒保肝的作用机制。方法：利用中药系统药理学分析平台（Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform，TCMSP）、中医药综合数据库（Traditional Chinese Medicines Integrated Database，TCMID）、中药分子机制生物信息学分析工具(A Bioinformatics Analysis Tool for Molecular MechANism of Traditional Chinese Medicine，BATMAN-TCM）、SwissTargetPrediction和TargetNet等数据库，检索益肝草凉茶中9味中药的活性成分及相关靶点；通过比较毒理基因组学数据库（The Comparative Toxicogenomics Database，CTD）、功能关联蛋白网络数据库（Functional Protein Association Networks，STRING）以及蛋白数据库（Universal Protein，Uniprot）数据库获取肝病相关的靶点；通过药物作用靶点及肝病靶点互作筛选益肝草凉茶解酒保肝的靶点，进一步构建解酒保肝靶点的蛋白相互作用网络；通过生物学信息注释数据库（Functional Annotation Bioinformatics Microarray Analysis，DAVID）数据库进行靶点蛋白的基因功能与通路分析；采用Cytoscape软件进行网络构建与分析；借助AutoDock软件，将关键成分与重要靶点进行分子对接验证。结果：本研究共收集到益肝草凉茶的活性成分186个，可作用于298个靶点，其中涉及到肝脏疾病的靶点有78个。预测靶点主要作用于癌症的途径、钙信号通路、神经活性配体-受体相互作用、5-羟色胺能突触、cGMP-PKG信号通路等通路发挥保肝护肝作用。结论：本研究揭示了益肝草凉茶可通过多成分、多靶点、多通路的作用特点调控网络发挥解酒保肝的功效，为其治疗酒精性肝病的研究和临床应用提供科学依据。Abstract: Objective: To explore the mechanism of relieving alcohol and protecting liver of Yigancao herbal tea by network pharmacology and molecular docking technology. Methods: The active components of 9 traditional Chinese medicines in Yigancao herbal teawere obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicines Integrated Database (TCMID) and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). The related targets were predicted by Swiss Target Prediction and Target Net databases, while the targets related to liver disease were collected by The Comparative Toxicogenomics Database (CTD), Functional Protein Association Network (STRING) and Uniprot database. The targets of Yigancao herbal tea were screened by drug action target and liver disease target interaction, and the protein interaction network of liver protection target was further constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the targets were analyzed using the Databasefor Annotation, Visualization and Integrated Discovery (DAVID), and the network was constructed and analyzed by Cytoscape software. With the help of Auto Dock software, the key components and important targets were verified by molecular docking. Results: The results showed that 186 active components of Yigancao herbal tea were screened and 298 targets were obtained, including 78 targets related to liver diseases. These targets were mainly involved in Pathways in cancer, Calcium signal pathway, Neuroactive ligand-receptor interaction, Serotonergic synapse, cGMP-PKG signaling pathway and other pathways to protect liver. Conclusion: This study revealled that Yigancao herbal tea could exert the effect of relieving alcohol and protecting liver through the regulation network of multi-components, multi-targets and multi-pathways, which provides a scientific basis for the research and clinical application of Yigancao herbal tea in the treatment of alcoholic liver disease.
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Key words:
- Yigancao herbal tea /
- relieving alcoholism /
- protecting liver /
- network pharmacology /
- molecular docking /
- mechanism
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图 1 益肝草凉茶解酒保肝作用的系统药理学流程图
Figure 1. Systematic pharmacological flow chart of antialcoholic and hepatoprotective effect of Yigancao herbal tea
图 2 中药-活性成分-靶点网络图
Figure 2. Network diagram of traditional Chinese medicine-active ingredient-target
注：V形代表中药，圆形代表活性成分，六边形代表靶点，四边形代表单味中药之间共有的活性成分。
图 3 疾病靶点在益肝草凉茶中9味中药的分布图
Figure 3. Distribution map of 9 traditional Chinese medicines in Yigancao herbal tea
图 5 活性成分相关靶点功能及通路注释分析
Figure 5. Analysis of target function and pathway annotation of active components
图 6 中药-活性成分-作用靶点-主要通路网络图
Figure 6. Network diagram of traditional Chinese medicine-active ingredient-action target-main pathway
图 7 NOS2、PTGS1、ESR1、CYP19A1与结合能排序最低的前2位化合物的最佳对接构象
Figure 7. The best docking conformation of NOS2, PTGS1, ESR1, CYP19A1 and the first two compounds with the lowest binding energy
表 1 中药-活性成分-靶点网络中度值排名前30的化合物信息
Table 1. Information of the top 30 compounds in the traditional Chinese medicine-active ingredient-target network
编号 PubChem CID 化合物名称 来源 度值 C9 5281855 鞣花酸（Ellagic acid） 覆盆子 84 C181 5460988 没食子酸（Gadelaidic acid） 甘草 79 C10 5280343 槲皮素（Quercetin） 甘草、枸杞子、大枣、栀子、
苦丁茶、鱼腥草、覆盆子，蒲公英73 C34 5363269 油酸乙酯（NF）（Ethyl oleate （NF）） 栀子 73 C180 3349565 二十碳五烯酸（Icos-5-enoic acid） 甘草 73 C53 5281707 香豆素（Coumestrol） 大枣 72 C31 5281232 番红花酸（Crocetin） 栀子 71 C11 5280863 山柰酚（Kaempferol） 甘草、栀子、苦丁茶、鱼腥草、覆盆子 69 C29 10970376 5-羟基-7-甲氧基-2-（3,4,5-三甲氧基苯基）
色原酮 （5-hydroxy-7-methoxy-2-（3,4,5-trimethoxyphenyl）chromone）栀子 69 C170 5318869 熊竹素（Jaranol） 甘草 69 C33 5282184 甘露醇（Mandenol） 枸杞子、栀子 67 C183 5317768 刺果甘草查耳酮（Glypallichalcone） 甘草 66 C98 N/A （E，E）-1-乙基十八烷基-3,13-二烯酸酯
（（E,E）-1-ethyl octadeca-3,13-dienoate）枸杞子 65 C162 5316900 槲皮素（Quercetin der.） 甘草 64 C30 5280862 3-甲基山柰酚（3-Methylkempferol） 栀子 63 C139 11558452 1,3-二羟基-9-甲氧基-6-苯并呋喃[3,2-c]
色原酮（1,3-dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromenone）甘草 62 C142 5318679 异槲皮酚（Isotrifoliol） 甘草 62 C182 5318999 甘草查耳酮B（Licochalcone B） 甘草 61 C52 10146 核黄素（Nuciferin） 大枣 59 C167 5281654 异鼠李素（Isorhamnetin） 甘草 58 C179 354368 7-甲氧基-2-甲基异黄酮 （7-Methoxy-2-methyl isoflavone） 甘草 58 C55 5280537 穆坪马兜铃酰胺（Moupinamide） 大枣 57 C92 N/A 7-O-甲基木犀草素-6-C-β-葡萄糖苷_qt （7-O-Methylluteolin-6-C-beta-glucoside_qt） 枸杞子 56 C159 10881804 （E）-1-（2,4-dihydroxyphenyl）-3-（2,2-dimethylchromen-6-yl）prop-2-en-1-one 甘草 56 C28 638072 角鲨烯（Supraene） 栀子 55 C127 15380912 kanzonols W 甘草 54 C176 92503 驴食草酚（Vestitol） 甘草 54 C172 25015742 7,2'，4'-三羟基－5-甲氧基－3－芳基香豆素
（7,2',4'-trihydroxy－5-methoxy-3－arylcoumarin）甘草 52 C6 5280378 芒柄花黄素（Formononetin） 甘草、葛根 51 C161 336327 苜蓿素（Medicarpin） 甘草 51 
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表 2 有效靶点作用于肝病的信息
Table 2. Information of effective targets acting on liver disease
疾病ID 疾病名称 疾病类别 注释基因数量 MESH:D008107 肝病 消化系统疾病 78 MESH:D008103 肝硬化 消化系统疾病|病理学（过程） 44 MESH:D008106 肝硬化，实验性 消化系统疾病|病理学（过程） 35 MESH:D008113 肝肿瘤 癌症|消化系统疾病 28 MESH:D006528 癌, 肝细胞 癌症|消化系统疾病 23 MESH:D056486 化学和药物诱导 消化系统疾病 17 MESH:D005234 肝损伤 消化系统疾病 13 MESH:D048550 脂肪肝 消化系统疾病 9 MESH:D065626 肝功能不全 消化系统疾病 8 MESH:D002780 非酒精性脂肪肝 消化系统疾病 7 MESH:D006501 胆汁淤积，肝内 消化系统疾病|代谢性疾病| 6 MESH:D017093 肝性脑病 神经系统疾病 6 MESH:D006529 肝衰竭 消化系统疾病 6 MESH:D008105 肝肿大 消化系统疾病|病理学（解剖条件） 5 MESH:D058625 肝硬化，胆汁性 消化系统疾病|病理学（过程） 3
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表 3 关键成分及对照药与NOS2、PTGS1、ESR1、CYP19A1的结合能
Table 3. Binding energy of key components and control drugs with NOS2, PTGS1, ESR1 and CYP19A1
类别 来源 化学成分 靶点 Energy of Binding
（kcal/mol）化学药物 熊去氧胆酸
胶囊熊去氧胆酸 NOS2 −3.83 PTGS1 −2.58 ESR1 −2.78 CYP19A1 −3.47 化学药物 双环醇片 双环醇 NOS2 −1.34 PTGS1 −1.28 ESR1 −0.51 CYP19A1 −1.73 中药 覆盆子 鞣花酸 NOS2 −1.80 PTGS1 −2.88 ESR1 −2.14 CYP19A1 −3.83 中药 甘草 没食子酸 NOS2 −0.13 PTGS1 −0.17 ESR1 0.52 CYP19A1 −0.58 中药 甘草，枸杞子，
大枣，栀子，
苦丁茶，鱼腥草，
覆盆子，蒲公英槲皮素 NOS2 −1.93 PTGS1 −2.44 ESR1 −1.65 CYP19A1 −2.23 中药 栀子 油酸乙酯 NOS2 0.29 PTGS1 0.27 ESR1 0.90 CYP19A1 0.78 中药 甘草 二十碳五烯酸 NOS2 −0.36 PTGS1 0.20 ESR1 0.73 CYP19A1 0.31 中药 大枣 香豆素 NOS2 −3.35 PTGS1 −3.19 ESR1 −3.25 CYP19A1 −3.96 中药 栀子 番红花酸 NOS2 −2.16 PTGS1 −2.97 ESR1 −2.86 CYP19A1 −2.08 中药 甘草、栀子、
苦丁茶、鱼腥草、
覆盆子山柰酚 NOS2 −2.52 PTGS1 −2.59 ESR1 −2.33 CYP19A1 −2.21 中药 栀子 5-羟基-7-甲氧基-
2-（3,4,5-三甲氧基
苯基）色原酮NOS2 −2.24 PTGS1 −2.08 ESR1 −1.89 CYP19A1 −2.27 中药 甘草 熊竹素 NOS2 −1.90 PTGS1 −2.51 ESR1 −2.46 CYP19A1 −2.41
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