基于网络药理学及分子对接探究茵栀黄颗粒治疗肝纤维化的作用机制

doi:10.3976/j.issn.1002-4026.2023.01.004

摘要/Abstract

摘要：

运用网络药理学及分子对接方法,探讨茵栀黄颗粒治疗肝纤维化的作用机制。通过中药系统药理学数据库与分析平台,对茵栀黄颗粒中4味药材进行活性成分筛选,利用SwissTargetPrediction数据库进行靶点预测;在GeneCards数据库中进行检索,获取肝纤维化相关的靶点,构建维恩图;运用DAVID数据库进行GO(gene ontology)功能和KEGG(Kyoto encyclopedia of genes and genomes)通路富集分析,运用Cytoscape3.9.0软件绘制成分-靶点网络图和靶点-通路网络图,通过STRING数据库与Cytoscape软件构建蛋白质-蛋白质相互作用网络图,利用AutoDock Tools对关键活性成分和核心靶点进行分子对接,验证网络药理学分析结果。通过口服生物利用度和类药性参数筛选出茵栀黄颗粒中的43个活性成分,肝纤维化相关靶点111个;GO功能富集分析得到生物过程条目346个,细胞组成条目32个,分子功能条目76个;KEGG通路富集分析筛选得到96条(P<0.05)信号通路,主要涉及PI3K-Akt信号通路、乙型肝炎、丙型肝炎、TNF信号通路等;分子对接显示茵栀黄颗粒中β-谷甾醇、木犀草素、山柰酚等与6个核心靶蛋白STAT3、AKT1、IL-6、TNF、EGFR、SRC均具有较好的亲和力。研究结果揭示茵栀黄颗粒多成分作用于多靶点,参与多通路的调控,通过抗炎、抑制氧化应激反应和抑制肝星状细胞的活化等发挥治疗肝纤维化的作用机制,该研究为进一步验证茵栀黄颗粒治疗肝纤维化的相关靶点及通路提供了依据。

关键词: 茵栀黄颗粒, 网络药理学, 分子对接, 肝纤维化

Abstract:

This study discussed the mechanism of action of Yinzhihuang Granules in the treatment of liver fibrosis using network pharmacology and molecular docking and aimed to provide further information regarding its basic research and clinical application.The active ingredients of Yinzhihuang Granules were screened using the traditional Chinese medicine systems pharmacology databases and analysis platforms. The targets were predicted using SwissTargetPrediction. By searching through the GeneCards database, liver fibrosis-related targets were screened out. Venn diagrams,Gene Ontology(GO) function, and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were conducted using DAVID. Ingredient-target and target-pathway networks were mapped using Cytoscape3.9.0. Protein-Protein interaction networks were built with the help of STRING and Cytoscape3.9.0. AutoDock Tools were used to perform molecular docking between the key active ingredients and core targets to verify the results of the network pharmacology analysis.Through oral bioavailability and drug-likeness parameters, 43 active ingredients and 111 liver fibrosis-related targets were screened from Yinzhihuang Granules; 346 biological process, 32 cellular composition, and 76 molecular function entries were filtered out from the GO functional enrichment analysis; 96 (P<0.05) signaling pathways, which mainly involved the PI3K-Akt signaling pathway, hepatitis B, hepatitis C, TNF signaling pathway, etc, were screened form the KEGG pathway enrichment analysis; and molecular docking showed that β-sitosterol, luteolin, and kaempferol present in Yinzhihuang Granules have good affinity with the 6 core target proteins: STAT3, AKT1, IL-6, TNF, EGFR, and SRC.The results revealed that YinzhihuangGranules act on multiple targets, participate in the regulation of multiple pathways, and play a role in the treatment of liver fibrosis via activating anti-inflammatory pathways, inhibiting oxidative stress response, and inhibiting the activation of hepatic stellate cells. This study provides evidence for the further validation of the targets and pathways of Yinzhihuang Granules that are involved in the treatment of liver fibrosis.

Key words: Yinzhihuang Granules, network pharmacology, molecular docking, liver fibrosis

中图分类号:

R285

申凤霞, 范建伟, 李倩, 马云, 冯群, 关永霞. 基于网络药理学及分子对接探究茵栀黄颗粒治疗肝纤维化的作用机制[J]. 山东科学, 2023, 36(1): 23-33.

SHEN Fengxia, FAN Jianwei, LI Qian, MA Yun, FENG Qun, GUAN Yongxia. Analysis of the mechanism of Yinzhihuang Granules in liver fibrosis treatment based on network pharmacology and molecular docking[J]. Shandong Science, 2023, 36(1): 23-33.

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编号	化合物名称	口服生物利用度(%)	类药性
MOL01	槲皮素	46.43	0.28
MOL03	β-谷甾醇	36.91	0.75
MOL04	绿原酸	31.93	0.33
MOL12	茵陈色原酮	57.56	0.31
MOL14	山奈酚	41.88	0.24
MOL21	栀子苷	34.64	0.44
MOL22	3-甲基山奈酚	60.16	0.26
MOL28	红花素	41.15	0.24
MOL32	二甲氧基黄酮	76.26	0.29
MOL33	4'-羟基汉黄芩素	36.56	0.27
MOL34	黄芩新素	104.34	0.44
MOL35	黄芩苷	30.53	0.77
MOL36	木犀草素	36.16	0.25
MOL37	山奈酚	41.88	0.24
MOL43	新绿原酸	30.65	0.33

靶点(PDB编号)	化合物	结合能/(kJ·mol^-1)	结合位点
STAT3(5AX3)	槲皮素	-34.28	ASP-158、TYR-27、MET-99、GLN-96
STAT3(5AX3)	木犀草素	-34.69	GLN-96、GLU-360、MET-99
STAT3(5AX3)	山柰酚	-33.44	GLN-96、GLU-62、GLU-360、MET-99、ASN-145
STAT3(5AX3)	黄芩苷	-38.87	GLN-96、MET-99、ASP-102、LYS-105
AKT1(1H10)	绿原酸	-37.62	ARG-23、ARG-86、ASN-53、ASN-54、GLN-79、LEU-52、TYR-18、ILE-19
TNF(5M2J)	黄芩苷	-35.11	GLN-47、ASN-46
EGFR(1XKK)	槲皮素	-37.20	LYS-745、ASP-855
EGFR(1XKK)	β-谷甾醇	-33.86	ARG-803
EGFR(1XKK)	木犀草素	-36.78	LYS-745、MET-793
EGFR(1XKK)	山柰酚	-36.37	LYS-745、MET-793、ASP-855
EGFR(1XKK)	绿原酸	-34.28	LYS-745、MET-793、CYS-797
EGFR(1XKK)	黄芩苷	-40.13	ALA-722、ARG-841、ASN-842、ASP-855