基于网络药理学和分子对接探讨益气活血方抗脑缺血机制研究

doi:10.5246/jcps.2022.02.010

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (2): 117-133.DOI: 10.5246/jcps.2022.02.010

基于网络药理学和分子对接探讨益气活血方抗脑缺血机制研究

商燕¹^,², 蔺晓源², 张田田¹^,², 谢丽华¹^,², 胡国恒¹^,²^,^*()

1. 湖南中医药大学, 湖南长沙 410208
2. 湖南中医药大学第一附属医院, 湖南长沙 410007

收稿日期:2021-09-18 修回日期:2021-09-25 接受日期:2021-10-29 出版日期:2022-02-27 发布日期:2022-02-25
通讯作者: 胡国恒
作者简介:
+ Tel.: +86-13974888299, E-mail: huguoheng@hnucm.edu.cn
基金资助:
General program of National Natural Science Foundation of China (Grant No. 81573941), Open fund project for first-class disciplines of traditional Chinese Medicine (Grant No. 2021ZYX20), and Graduate research innovation project of Hunan Province (Grant No. CX20200798).

Investigation on the mechanism of YQHX against cerebral ischemic injury based on network pharmacology and molecular docking

Yan Shang¹^,², Xiaoyuan Lin², Tiantian Zhang¹^,², Lihua Xie¹^,², Guoheng Hu¹^,²^,^*()

1 Hunan University of Chinese Medicine, Changsha 410208, China
2 The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China

Received:2021-09-18 Revised:2021-09-25 Accepted:2021-10-29 Online:2022-02-27 Published:2022-02-25
Contact: Guoheng Hu

摘要/Abstract

摘要：

脑缺血(cerebral ischemia, CI)具有高发病率、高致畸率, 是全球第二大致死疾病。中药(traditional Chinese medicine, TCM)益气活血方(YQHX)在临床治疗CI发挥一定疗效, 但其机制尚不清楚。本文基于网络药理学和分子对接探讨其作用机制。通过TCMSP和CNKI数据库获取益气活血方活性成分; 利用Pharmmapper数据库获得成分靶点信息; 检索OMIM、GeneCards、DisGeNET数据库得到脑缺血的疾病靶点; Venn图得到交集靶点, Cytoscape可视化结果, 插件MCODE获得核心靶点; 使用Metascape数据库对核心靶点进行GO和KEGG通路富集分析; 选取前20条KEGG通路富集通路用Cytoscape构建 "成分-靶点-通路"图; 排名前10的成分与前5的靶点信息, 利用AutoDock Vina软件进行分子对接验证, 用PyMoL、Ligplus软件可视化结果。筛选得到益气活血方活性成分83个, 相应靶点432个, 疾病相关靶点2005个, 药物与疾病的交集靶点140个; 通过GO生物功能分析和KEGG通路富集分析得到507 条生物功能条目及141条信号通路。KEGG通路富集分析主要参与细胞增殖、粘附、迁移等过程; 分子对接结果显示, 筛选的关键成分与核心靶点皆具备较强的结合活性, 其中EGFR、MAP2K1、KDR与丹参新酮I、丹参酮二酚结合较为稳定。益气活血方治疗脑缺血主要生物学机制可能通过酪氨酸激酶受体相关的信号通路发挥作用, 也是对中医"益气活血, 血脉新生"理论的完善。

关键词: 网络药理学, 分子对接, 益气活血方, 脑缺血, 机制

Abstract:

Cerebral ischemia (CI) is the world’s second-largest lethal disease, with a high recurrence and teratogenic rate. Traditional Chinese medicine (TCM) YQHX (a pharmaceutical preparation from herbs) has a certain effect in the clinical treatment of CI, while its underlying mechanism remains largely undetermined. To explore the potential mechanism, we used network pharmacology and molecular docking in the present study. TCMSP and CNKI databases were used to explore the active ingredients of YQHX; the Pharmmapper database was used to get the ingredient targets; the OMIM, GeneCards, and DisGeNET databases were used to obtain the disease targets; the Venn diagram was used to obtain the intersection targets, the Cytoscape was used to visualize results and plug-in MCODE to obtain core targets; the Metascape database was used to perform GO and KEGG pathway enrichment analyses on core targets. The top 20 KEGG pathway enrichment pathways were used to construct the "ingredient-target-pathway" network by Cytoscape; the top 10 ingredients and the top five protein targets were used for molecular docking with AutoDock Vina software, and PyMoL and Ligplus software were used to visualize the results. A total of 83 active ingredients were screened from YQHX. Moreover, 432 corresponding targets, 2005 disease-related targets, and 140 drug-disease intersection targets were obtained. GO biological function and KEGG pathway enrichment analyses yielded 507 biological function entries and 141 signaling pathways. KEGG pathway enrichment was mainly involved in cell proliferation, adhesion, migration, and other processes. Molecular docking results showed that the key ingredients and core targets screened had a strong binding activity, including EGFR, MAP2K1, and KDR. The combination of miltionone I and miltiodiol was relatively stable. The main biological mechanism of YQHX in the treatment of CI might play a role through the signaling pathway related to the tyrosine kinase receptor, which was also the improvement of the theory of "benefiting qi and activating blood circulation for promoting the production of blood and blood vessels".

Key words: Network pharmacology, Molecular docking, YQHX, Cerebral ischemia, Mechanism

Supporting:

商燕, 蔺晓源, 张田田, 谢丽华, 胡国恒. 基于网络药理学和分子对接探讨益气活血方抗脑缺血机制研究[J]. 中国药学(英文版), 2022, 31(2): 117-133.

Yan Shang, Xiaoyuan Lin, Tiantian Zhang, Lihua Xie, Guoheng Hu. Investigation on the mechanism of YQHX against cerebral ischemic injury based on network pharmacology and molecular docking[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(2): 117-133.

图/表 14

Figure 1. Flowchart of the current study.

Table 1. Information of 83 active ingredients in YQHX.

Figure 2. Venn diagram of YQHX targets and CI targets.

Figure 3. Network diagram of YQHX components and pharmacodynamic targets.The pink nodes represent Ligusticum wallichii, the light blue nodes represent Salvia miltiorrhiza, the purple nodes represent the Angelica sinensis, the green nodes represent Astragalus mongholicus, the yellow nodes represent the common ingredients, the node shape size represents the number of interactions.

Table 2. Top 10 active ingredients and targets of YQHX.

Figure 4. PPI network diagram of protein targets of YQHX. The circle nodes represent the protein targets, and the circle size and color depth represents the protein interaction of the targets.

Table 3. The core target of YQHX cluster 1.

Figure 5. Top 10 BP, CC, MF of GO enrichment analysis. The Y-axis of A is sorted by gene enrichment; the Y-axis of B is sorted by P value, and the X-axis indicates go enrichment items.

Figure 6. Top 20 pathways of KEGG pathway enrichment analysis. The X-axis represents the number of genes enriched to a specific pathway; the Y-axis represents the classification of pathways.

Table 4. Top 20 pathways based on KEGG pathway enrichment analysis.

Figure 7. Analysis of focal adhesion pathway.

Figure 8. The ingredients-targets-pathways network of YQHX. Octagonal nodes represent components, rhombic nodes represent protein targets, square nodes represent pathways, and the size and color of nodes represent the number of interactions.

Table 5. Docking results of YQHX main ingredients with the key target.

Figure 9. Molecular docking diagram of YQHX components and key targets. A is miltionone I and EGFR, B is miltiodiol and MAP2K1, C is miltiodiol and KDR; A1/A2, B1/B2, C1/C2 is PyMOL 3D, A3, B3, C3 is ligplus 2D; dotted line is hydrogen bond connection.

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基于网络药理学和分子对接探讨益气活血方抗脑缺血机制研究

Investigation on the mechanism of YQHX against cerebral ischemic injury based on network pharmacology and molecular docking

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