基于网络药理学和分子对接技术探讨雷公藤卵巢毒性的机制

doi:10.3724/zdxbyxb-2021-0230

浙江大学学报（医学版）

2022, Vol. 51

Issue (1): 62-72 DOI: 10.3724/zdxbyxb-2021-0230

中药现代化

基于网络药理学和分子对接技术探讨雷公藤卵巢毒性的机制

王志强^1,²,宫彩霞³,李振彬^1,^2,*(

)

1.中国人民解放军联勤保障部队第九八〇医院风湿免疫科，河北石家庄 050082
2.南京中医药大学第一临床医学院，江苏南京 210023
3.石家庄平安医院肾脏病科，河北石家庄 050012

Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking

WANG Zhiqiang^1,²,GONG Caixia³,LI Zhenbin^1,^2,*(

)

1. Department of Rheumatology and Clinical Immunology, the 980th Hospital of the Joint Logistic Support Force of the People’s Liberation Army, Shijiazhuang 050082, China;
2. First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China;
3. Department of Nephrology, Shijiazhuang Ping’an Hospital, Shijiazhuang 050012, China

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摘要：

目的：通过网络药理学和分子对接技术探讨雷公藤卵巢毒性的作用机制。方法：通过中药系统药理数据库及分析平台（TCMSP）和比较毒理基因组学数据库（CTD）收集雷公藤的候选毒性化合物和靶点，从CTD中获得雷公藤潜在的卵巢毒性靶点，并利用STRING数据库对雷公藤卵巢毒性的靶点基因进行分析。用Cytoscape软件构建蛋白质-蛋白质相互作用（PPI）网络，用cytoHubba插件鉴定核心基因。此外，利用R软件对雷公藤卵巢毒性的靶点基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。最后，使用Discovery Studio软件对核心毒性化合物和核心基因进行分子对接验证。结果：共获得9个雷公藤候选毒性化合物和56个潜在的卵巢毒性靶点。网络分析结果，雷公藤甲素、山柰酚和雷公藤红素是雷公藤的关键卵巢毒性化合物，核心卵巢毒性基因包括TP53、MYC、PTEN、MAPK3、MTOR、STAT3、EGFR、KRAS、CDH1和AKT1。GO和KEGG分析显示，雷公藤通过氧化应激、生殖系统发育和功能、细胞周期调节、对内源性激素和外源性刺激的反应、细胞凋亡调节、衰老等途径引起卵巢毒性。分子对接研究显示，雷公藤的3个关键卵巢毒性化合物可与10个核心基因的对接口袋相匹配。结论：雷公藤可能通过作用于10个核心基因和140条信号通路而导致卵巢毒性。

关键词： 雷公藤; 卵巢毒性; 网络药理学; 靶点; 通路

Abstract:

Objective: To explore the mechanism of ovarian toxicity of Tripterygium wilfordii Hook. F. (TwHF) by network pharmacology and molecular docking. Methods: The candidate toxic compounds and targets of TwHF were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Comparative Toxicogenomics Database (CTD). Then, the potential ovarian toxic targets were obtained from CTD, and the target genes of ovarian toxicity of TwHF were analyzed using the STRING database. The protein-protein interaction (PPI) network was established by Cytoscape and analyzed by the cytoHubba plug-in to identify hub genes. Additionally, the target genes of ovarian toxicity of TwHF were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses by using the R software. Finally, Discovery Studio software was used for molecular docking verification of the core toxic compounds and the hub genes. Results: Nine candidate toxic compounds of TwHF and 56 potential ovarian toxic targets were identified in this study. Further network analysis showed that the core ovarian toxic compounds of TwHF were triptolide, kaempferol and tripterine, and the hub ovarian toxic genes included TP53, MYC, PTEN, MAPK3, MTOR, STAT3, EGFR, KRAS, CDH1 and AKT1. Besides, the GO and KEGG analysis indicated that TwHF caused ovarian toxicity through oxidative stress, reproductive system development and function, regulation of cell cycle, response to endogenous hormones and exogenous stimuli, apoptosis regulation and aging. The docking studies suggested that 3 core ovarian toxic compounds of TwHF were able to fit in the binding pocket of the 10 hub genes. Conclusion: TwHF may cause ovarian toxicity by acting on 10 hub genes and 140 signaling pathways.

Key words: Tripterygium wilfordii Hook.F. Ovarian toxicity Network pharmacology Target Pathway

收稿日期: 2021-08-08 出版日期: 2022-05-17

CLC:

R285.5

基金资助: 国家自然科学基金（81873301）

通讯作者: 李振彬 E-mail: lizb1962@126.com

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引用本文:

王志强,宫彩霞,李振彬. 基于网络药理学和分子对接技术探讨雷公藤卵巢毒性的机制[J]. 浙江大学学报（医学版）, 2022, 51(1): 62-72.

WANG Zhiqiang,GONG Caixia,LI Zhenbin. Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking. J Zhejiang Univ (Med Sci), 2022, 51(1): 62-72.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0230 或 https://www.zjujournals.com/med/CN/Y2022/V51/I1/62

表 1 雷公藤候选毒性化合物及对应靶点数

图 1 雷公藤毒性化合物–卵巢毒性靶点网络绿色六边形表示活性化合物，红色圆形表示靶点.

图 2 雷公藤卵巢毒性靶点的蛋白质–蛋白质相互作用网络节点的颜色和大小按照度值由高到低的顺序依次由红到黄、由大到小标示.

表 2 雷公藤卵巢毒性靶点的蛋白质–蛋白质相互作用网络中核心基因信息

图 3 雷公藤卵巢毒性靶点的基因本体（GO）富集分析结果排序前二十条目

图 4 雷公藤卵巢毒性靶点的KEGG通路富集分析结果排序前二十信号通路KEGG：京都基因与基因组百科全书.

图 5 雷公藤甲素与卵巢毒性核心靶点基因的分子对接模式图黄色结构为雷公藤甲素，彩色结构为卵巢毒性核心靶点基因分子.

表 3 雷公藤核心毒性化合物与核心卵巢毒性靶点基因分子对接的CDOCKER相互作用能

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