基于网络药理学与分子对接探索人参-五味子配伍治疗特发性肺间质纤维化的分子机制

doi:10.3976/j.issn.1002-4026.2022.01.005

摘要/Abstract

摘要：

基于网络药理学与分子对接方法,探讨中药人参-五味子配伍治疗特发性肺间质纤维化(idiopathic pulmonary fibrosis,IPF)的潜在分子机制。通过GeneCards、CTD、GEO等数据库预测IPF疾病靶标基因,从TCMSP平台筛选人参-五味子有效活性成分及其治疗靶标,构建中药-活性成分-靶标基因调控网络。通过STRING网站分析靶标基因蛋白质-蛋白质相互作用( protein-protein interaction, PPI)关系并筛选出其中的关键基因;通过SwissDock在线平台进行关键靶标与有效活性成分的分子对接,验证评估其结合潜力;利用R语言进行关键基因的基因本体( gene ontology, GO)功能注释与基于京都基因与基因组百科全书 ( Kyoto encyclopedia of genes and genomes, KEGG)信号通路富集分析。结果表明:共筛选获得人参-五味子含山奈酚、豆甾醇等23个有效活性成分,作用于48个IPF靶标基因,并从靶标基因PPI网络中筛选获得AKT1、PTGS2、IL1B等20个关键基因,关键基因与药对活性成分分子对接能量稳定,结合牢固;关键基因主要富集于核受体活性、类固醇受体活性等67个GO生物学过程,以及白介素17信号通路、肿瘤坏死因子TNF信号通路等90个KEGG信号通路。人参-五味子配伍益气养阴,其可能通过调节机体免疫、抗纤维化、抗氧化应激、抑制炎症等多通路机制发挥治疗IPF的作用。

关键词: 人参, 五味子, 特发性肺间质纤维化, 网络药理学, 分子对接

Abstract:

Based on the network pharmacology and molecular docking study approach, investigation of the potential molecular mechanism of Ginseng Radix Et Rhizoma-Schisandrae Chinensis Fructus couple medicine in the treatment of idiopathic pulmonary fibrosis (IPF) was conducted. The active ingredients and therapeutic targets of Ginseng Radix Et Rhizoma-Schisandrae Chinensis Fructus couple medicine were selected on a TCM systematic pharmacological analysis platform. The disease targets corresponding to IPF were obtained from the Gene Expression Omnibus, GeneCards and CTD databases. The protein-protein interaction(PPI) network was constructed and analyzed using the STRING online database. Gene ontology(GO) analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analyses of the hub genes were conducted using R language. Overall, 23 active ingredients of Ginseng Radix Et Rhizoma-Schisandrae Chinensis Fructus couple medicine were screened; these active ingredients acted on 48 IPF target genes. Twenty hub genes such as AKT1, PTGS2, and IL1B were screened from the PPI network of target genes, and the docking energy of hub genes and active ingredient molecules of the drug pair were stable and firmly bound. The hub genes were enriched in 67 GO processes, including nuclear receptor activity and steroid receptor activity, and 90 KEGG signaling pathways, such as IL17 signaling pathway and tumor necrosis factor signaling pathway. The combination of Ginseng Radix Et Rhizoma and Schisandrae Chinensis Fructus reinforces Qi and nourishes Yin, which may exert its effects on the treatment of IPF through multiple pathways and mechanisms such as regulation of body immunity, antifibrosis, antioxidative stress, and inhibition of inflammation.

Key words: Ginseng Radix Et Rhizoma, Schisandrae Chinensis Fructus, idiopathic pulmonary fibrosis, network pharmacology, molecular docking

中图分类号:

R285

顾一丹,任允琰,章朱峰,高平. 基于网络药理学与分子对接探索人参-五味子配伍治疗特发性肺间质纤维化的分子机制[J]. 山东科学, 2022, 35(1): 28-36.

GU Yi-dan,REN Yun-yan,ZHANG Zhu-feng,GAO Ping. Molecular mechanism of Ginseng Radix Et Rhizoma-Schisandrae Chinensis Fructus couple medicine in the treatment of idiopathic pulmonary fibrosis based on network pharmacology and molecular docking[J]. Shandong Science, 2022, 35(1): 28-36.

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序号	成分代码	成分名称	OB/%	DL	来源
1	MOL002879	己二酸二异辛酯	43.59	0.39	人参
2	MOL000449	豆甾醇	43.83	0.76	人参
3	MOL000358	β-谷甾醇	36.91	0.75	人参
4	MOL003648	高丽槐素	65.83	0.54	人参
5	MOL000422	山柰酚	41.88	0.24	人参
6	MOL005308	阿朴天仙子碱	66.65	0.22	人参
7	MOL005318	石竹胺	40.45	0.2	人参
8	MOL005320	花生四烯酸	45.57	0.2	人参
9	MOL005321	佛丁酮A	65.9	0.34	人参
10	MOL005344	人参皂苷rh2	36.32	0.56	人参
11	MOL005348	人参皂苷-Rh4苷元	31.11	0.78	人参
12	MOL005356	吉九里香碱	61.22	0.31	人参
13	MOL005376	人参萜二醇	33.09	0.79	人参
14	MOL005384	苏卡内酯	57.52	0.56	人参
15	MOL005399	胡萝卜甙	36.91	0.75	人参
16	MOL000787	蓝堇碱	59.26	0.83	人参
17	MOL005317	脱氧三尖杉酯碱	39.27	0.81	共同
18	MOL008957	五味子素B	30.71	0.83	五味子
19	MOL008968	五味子醇A	30.69	0.78	五味子
20	MOL008978	五味子醇R	34.84	0.86	五味子
21	MOL008992	五味子素C	46.27	0.84	五味子
22	MOL009213	五味子木脂素B	30.63	0.84	五味子
23	MOL009220	新南五味子素	33.35	0.88	五味子

序号	通路编号	通路名称	富集基因数	P值	富集基因
1	hsa04657	白介素17信号通路	8	2.22×10^-9	JUN, CASP8, MMP1, IFNG, CASP3, PTGS2, IL1B, MAPK8
2	hsa04668	肿瘤坏死因子信号通路	8	4.62×10^-9	ICAM1, JUN, CASP8, AKT1, CASP3, PTGS2, IL1B, MAPK8
3	hsa05418	流体剪切应力和动脉粥样硬化	7	7.40×10^-8	ICAM1, JUN, CASP8, AKT1, CASP3, PTGS2, IL1B
4	hsa04933	糖尿病并发症AGE-RAGE信号通路	6	1.63×10^-6	ICAM1, JUN, AKT1, CASP3, IL1B, MAPK8
5	hsa04625	C型凝集素受体信号通路	6	1.66×10^-6	JUN, CASP8, AKT1, PTGS2, IL1B, MAPK8
6	hsa05152	肺结核	6	1.66×10^-6	CASP8, AKT1, NOS2, IFNG, CASP3, IL1B
7	hsa04380	破骨细胞分化	6	3.55×10^-6	JUN, AKT1, IFNG, IL1B, MAPK8, PPARG
8	hsa05145	麻疹	6	5.04×10^-6	CASP8, AKT1, NOS2, IFNG, CASP3, MAPK8
9	hsa05133	百日咳	5	5.71×10^-6	JUN, NOS2, CASP3, IL1B, MAPK8
10	hsa05164	甲型流感	6	1.19×10^-5	ICAM1, CASP8, AKT1, IFNG, CASP3, IL1B

序号	关键靶点	活性成分	对接能量ΔG/(kJ·mol^-1)
1	AKT1	山奈酚(Kaempferol)	-30.14
2		豆甾醇(Stigmasterol)	-33.86
3		β-谷甾醇(Beta-sitosterol)	-36.21
4		高丽槐素(Inermin)	-32.98
5		山奈酚(Kaempferol)	-30.43
6		石竹胺(Dianthramine)	-30.39
7	PTGS2	花生四烯酸(Arachidonate)	-34.07
8		佛丁酮A (Frutinone A)	-29.30
9		人参皂苷rh2(Ginsenoside rh2)	-39.77
10		吉九里香碱(Girinimbin)	-32.78
11		苏卡内酯(Suchilactone)	-34.58
12		蓝堇碱(Fumarine)	-30.05
13		五味子素B (Schizandrer B)	-36.46
14	IL1B	人参皂苷rh2(Ginsenoside rh2)	-29.01
15	MAPK8	山奈酚(Kaempferol)	-31.23
16		β-谷甾醇(Beta-sitosterol)	-28.17
17	CASP3	山奈酚(Kaempferol)	-26.96
18		人参皂苷rh2(Ginsenoside rh2)	-29.43