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浙江大学学报（医学版）
浙江大学学报（医学版）  2020, Vol. 49 Issue (6): 714-724    DOI: 10.3785/j.issn.1008-9292.2020.12.06
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基于网络药理学和分子对接技术探讨葛花-枳椇子治疗酒精性肝损伤的潜在作用机制
汪亚楠1(),闫孝明2(),张晴宇1,宋爱华1,韩飞1,*()
1. 沈阳药科大学药学院, 辽宁 沈阳 110016
2. 山东省济宁市任城区人民医院骨外科, 山东 济宁 272000
Study on the mechanism of Flos Puerariae and Semen Hoveniae in treatment of alcoholic liver injury based on network pharmacology and molecular docking
WANG Yanan1(),YAN Xiaoming2(),ZHANG Qingyu1,SONG Aihua1,HAN Fei1,*()
1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
2. Department of Orthopedics, Jining Rencheng District People's Hospital, Jining 272000, Shandong Province, China
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摘要：

目的: 利用网络药理学和分子对接技术对葛花-枳椇子治疗酒精性肝损伤（ALI）的潜在作用机制进行研究。方法: 先利用中药系统药理学数据库与分析平台（TCMSP）和Swiss数据库搜集与葛花、枳椇子药材相关的化学成分及作用靶点，并以口服利用度（OB）≥30%和类药性（DL）≥0.18对化合物进行筛选；同时，使用GeneCard、DrugBank数据库获取与ALI相关的靶点，借助韦恩图映射葛花-枳椇子治疗ALI的潜在作用靶点，再采用String数据库和Cytoscape软件构建蛋白-蛋白相互作用网络及“药材-潜在活性成分-作用靶点”相互作用网络；接着在DAVID和Reactome数据库中对潜在作用靶点进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析；最后，使用AutoDock Vina软件将潜在活性成分与核心靶点进行分子对接验证。结果: 在葛花-枳椇子中，共筛选出21个与疾病相关的潜在活性成分和431个潜在作用靶点，涉及蛋白结合、ATP结合等273种生物功能及磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）信号通路、TNF信号通路等90条KEGG代谢通路和信号转导、免疫系统等362条Reactome通路。分子对接结果显示，21个潜在活性成分与核心靶点蛋白激酶B（Akt）1、肿瘤蛋白p53（TP53）、IL-6均有较好的亲和力。结论: 本研究结果揭示了葛花-枳椇子治疗ALI的多成分、多靶点、多途径的作用特点，并预测了可能的药效物质、关键靶点和作用通路，为其新药开发和作用机制研究提供了理论基础。
关键词： 酒精性肝损伤;  葛花-枳椇子;  网络药理学;  分子对接;  作用机制    
Abstract:

Objective: To explore the mechanism of Flos Puerariae and Semen Hoveniae in treatment of alcoholic liver injury (ALI) based on network pharmacology and molecular docking. Methods: The information of chemical constituents and targets of Flos Puerariae and Semen Hoveniae was collected from TCMSP and Swiss databases, and the threshold values of oral bioavailability (OB) ≥ 30%, drug likeness (DL) ≥0.18 were used to screen the potential active compounds. The GeneCard and DrugBank databases were used to obtain the targets corresponding to ALI. The common targets were queried using Venn Diagram, and the network of PPI and Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed through DAVID and Reactome database. Autodock Vina software was used for molecular docking of potential ingredients and key targets. Results: A total of 21 potential active compounds and 431 therapeutic targets were gathered in Flos Puerariae and Semen Hoveniae, which involved 273 biological functions, 90 KEGG pathways and 362 Reactome pathways. The GO functions involved protein binding, ATP binding, etc.; the KEGG pathways mainly included PI3K-Akt signaling pathway and TNF signaling pathway; the Reactome pathways contained signal transduction and immune system, etc. The results of molecular docking showed that 21 potential active ingredients had good affinity with the core targets Akt1, TP53 and IL-6. Conclusion: The network pharmacology and molecular docking analysis demonstrate the synergetic effect of Flos Puerariae and Semen Hoveniae with multi-compounds, multi-targets and multi-pathways in the treatment of ALI; and also predict the possible medicinal substance, key targets and pathways, which provides clues for the new drug development and mechanism research.
Key words: Alcoholic liver injury    Flos Puerariae and Semen Hoveniae    Network pharmacology    Molecular docking    Mechanism
收稿日期: 2020-10-11 出版日期: 2021-01-14
CLC:  R285  
通讯作者: 韩飞     E-mail: 1334423511@qq.com;13854780111@163.com;hanfei_spu@163.com
作者简介: 汪亚楠(1995-), 女, 硕士研究生, 主要从事药物分析研究; E-mail:1334423511@qq.com; https://orcid.org/0000-0001-7160-4133|闫孝明(1975-), 男, 学士, 主治医师, 主要从事骨外科临床工作及分子对接研究; E-mail:13854780111@163.com; https://orcid.org/0000-0002-7196-5999
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引用本文:

汪亚楠,闫孝明,张晴宇,宋爱华,韩飞. 基于网络药理学和分子对接技术探讨葛花-枳椇子治疗酒精性肝损伤的潜在作用机制[J]. 浙江大学学报（医学版）, 2020, 49(6): 714-724.

WANG Yanan,YAN Xiaoming,ZHANG Qingyu,SONG Aihua,HAN Fei. Study on the mechanism of Flos Puerariae and Semen Hoveniae in treatment of alcoholic liver injury based on network pharmacology and molecular docking. J Zhejiang Univ (Med Sci), 2020, 49(6): 714-724.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.12.06    或    http://www.zjujournals.com/med/CN/Y2020/V49/I6/714

序号 MOL ID 名称 分子式 口服生物利用度(%) 类药性 度值 介数值 来源
1 MOL000098 槲皮素 C15H10O7 46.43 0.28 201 0.3888 葛花、枳椇子
2 MOL000422 山柰酚 C15H10O6 41.88 0.24 130 0.1328 葛花、枳椇子
3 MOL004328 柚皮素 C15H12O5 59.29 0.21 101 0.1293 枳椇子
4 MOL004957 异芒柄花素 C16H12O4 38.37 0.21 96 0.1373 葛花
5 MOL001749 邻苯二甲酸二辛酯 C24H38O4 43.59 0.35 92 0.1902 葛花
6 MOL001792 甘草素 C15H12O4 32.76 0.18 86 0.0823 葛花
7 MOL012976 香豆雌酚 C15H8O5 32.49 0.34 73 0.0697 葛花
8 MOL000358 β-谷甾醇 C29H50O 36.91 0.75 71 0.0664 葛花、枳椇子
9 MOL000392 刺芒柄花素 C16H12O4 69.67 0.21 69 0.0505 葛花
10 MOL005916 尼泊尔鸢尾黄素 C17H14O6 37.78 0.30 67 0.0382 葛花
11 MOL008400 黄豆黄素 C16H12O5 50.48 0.24 65 0.0489 葛花
12 MOL000449 豆甾醇 C29H48O 43.83 0.76 64 0.0579 葛花、枳椇子
13 MOL000468 8-甲雷杜辛 C17H14O5 70.32 0.27 60 0.0285 葛花
14 MOL002959 3′-甲氧基大豆苷元 C16H12O5 48.57 0.24 55 0.0177 葛花
15 MOL000359 谷甾醇 C29H50O 36.91 0.75 43 0.0216 葛花
16 MOL008034 美洲茶酸 C30H46O5 73.52 0.77 33 0.0339 枳椇子
17 MOL011793 葛花亭 C16H14O5 55.25 0.24 24 0.0092 葛花
18 MOL011791 葛花苷 C28H32O15 46.91 0.67 12 0.0051 葛花
19 MOL003629 大豆苷元-4, 7-二葡萄糖苷 C27H30O14 47.27 0.67 8 0.0004 葛花
20 MOL013305 鹰嘴豆醇 C15H12O5 83.67 0.21 4 4.830-5 葛花
21 MOL002140 川芎哚 C16H12N2O2 65.95 0.27 3 6.703-5 枳椇子
表 1  葛花-枳椇子的21个潜在活性成分及其基本信息
图 1  葛花-枳椇子治疗酒精性肝损伤的潜在作用靶点蛋白-蛋白相互作用网络
图 2  葛花-枳椇子治疗酒精性肝损伤“药材-潜在活性成分-作用靶点”相互作用网络
图 3  葛花-枳椇子治疗酒精性肝损伤前20条基因本体富集通路
图 4  葛花-枳椇子治疗酒精性肝损伤前20条KEGG富集通路
图 5  葛花-枳椇子治疗酒精性肝损伤的Reactome通路分析结果
通路 名称 基因数 P值 错误发现率
R-HSA-162582 信号转导 246 1.11-16 1.73-14
R-HSA-168256 免疫系统 208 4.01-14 4.81-12
R-HSA-74160 基因表达 175 1.11-16 1.73-14
R-HSA-212436 基因转录途径 174 1.11-16 1.73-14
R-HSA-73857 RNA聚合酶Ⅱ转录 174 1.11-16 1.73-14
R-HSA-1280215 免疫系统中细胞因子的信号传导 156 1.11-16 1.73-14
R-HSA-1643685 疾病 136 1.77-03 8.84-03
R-HSA-449147 白细胞介素信号 124 1.11-16 1.73-14
R-HSA-556833 脂质代谢 91 4.50-04 3.15-03
R-HSA-168249 先天免疫系统 85 4.41-04 3.09-03
R-HSA-9006934 受体酪氨酸激酶信号转导 81 1.11-16 1.73-14
R-HSA-388396 G蛋白偶联受体下游信号 79 8.35-03 3.12-02
R-HSA-6785807 IL-4和IL-13信号转导 78 1.11-16 1.73-14
R-HSA-1266738 发育生物学 75 4.12-03 1.65-02
R-HSA-8953897 细胞对外界刺激的反应 65 4.22-08 1.35-06
R-HSA-109582 止血 64 1.28-05 1.41-04
R-HSA-2262752 细胞应激反应 64 3.75-08 1.20-06
R-HSA-9006931 核受体信号传递 62 1.11-16 1.73-14
R-HSA-1640170 细胞周期 60 5.46-06 6.55-05
R-HSA-5663202 生长因子受体和第二信使信号转导的疾病 57 1.62-10 1.06-08
表 2  葛花-枳椇子治疗酒精性肝损伤前20条Reactome通路
MOL ID 化合物 结合能
Akt1 TP53 IL-6
Akt：蛋白激酶B；TP53：肿瘤蛋白p53.
MOL000098 槲皮素 -38.04 -33.02 -31.35
MOL000358 β-谷甾醇 -33.44 -28.01 -26.75
MOL000359 谷甾醇 -44.31 -28.01 -30.10
MOL000392 刺芒柄花素 -40.13 -28.42 -28.84
MOL000422 山柰酚 -38.46 -30.10 -30.93
MOL000449 豆甾醇 -33.44 -28.84 -29.68
MOL000468 8-甲雷杜辛 -39.29 -26.33 -28.42
MOL001749 邻苯二甲酸二辛酯 -32.60 -21.74 -24.24
MOL001792 甘草素 -35.53 -30.10 -28.01
MOL002140 川芎哚 -40.13 -31.77 -29.68
MOL002959 3′-甲氧基大豆苷元 -40.13 -30.10 -29.68
MOL003629 大豆苷元-4, 7-二葡萄糖苷 -43.05 -33.02 -30.93
MOL004328 柚皮素 -31.35 -29.26 -28.42
MOL004957 异芒柄花素 -39.29 -28.42 -28.84
MOL005916 尼泊尔鸢尾黄素 -38.46 -29.26 -26.75
MOL008034 美洲茶酸 -34.28 -31.77 -30.93
MOL008400 黄豆黄素 -39.71 -30.10 -31.35
MOL011791 葛花苷 -45.56 -30.10 -32.19
MOL011793 葛花亭 -37.20 -28.84 -28.42
MOL012976 香豆雌酚 -43.47 -28.84 -31.35
MOL013305 鹰嘴豆醇 -36.37 -30.51 -30.10
表 3  葛花-枳椇子核心化合物与靶蛋白AK1、TP53和IL-6的分子对接结果
图 6  葛花-枳椇子潜在活性成分与核心靶点的分子对接分析
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