基于网络药理学的猫爪草治疗结核病作用机制研究

doi:10.3976/j.issn.1002-4026.2021.06.007

摘要/Abstract

摘要：

通过网络药理学方法探讨猫爪草治疗结核病的作用机制。运用中药系统药理学数据库与分析平台筛选猫爪草的活性成分和相关作用靶点;借助GeneCards数据库检索疾病靶点,活性成分靶点与疾病靶点作交集得到猫爪草作用于结核病的预测靶点;运用STRING数据库构建蛋白质-蛋白质相互作用网络图;将交集基因进行基因本体分析和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析;最后应用AutoDock软件进行活性成分及潜在靶点之间的分子对接验证。筛选得到猫爪草的活性化合物12个,其有效活性成分主要作用于结核病的关键靶点有CASP3、CASP8、CASP9、BCL2和BAX。KEGG结果表明,猫爪草可能通过调节细胞凋亡信号通路从而对结核病进行干预。分子对接得到猫爪草的主要成分是豆甾-4,6,8、维太菊苷、豆甾醇、豆甾醇葡萄糖苷、谷甾醇乙酸酯和β-谷甾醇,对BAX、CASP3和CASP9作用明显。本研究从分子水平探讨了猫爪草治疗结核病的活性成分与潜在靶点,初步验证了其作用机制。

关键词: 网络药理学, 猫爪草, 结核病, 信号通路, 分子对接

Abstract:

This study aimed to investigate the mechanism of Ranunculi Ternati Radix in the treatment of tuberculosis based on network pharmacology. The active ingredients and related targets of Ranunculi Ternati Radix were screened using the Traditional Chinese Medicine System Pharmacology database and analysis platform. With the help of the GeneCards database to search disease targets, the intersections of active ingredient targets and disease targets are used as the predicted targets of Ranunculi Ternati Radix for tuberculosis treatment. A protein-protein interaction network diagram was constructed using the STRING database, and gene ontoeogy and Kyoto encyclopedia of gene and genomes(KEGG) enrichment analyses were performed for the overlapping genes. Finally, molecular docking verification between active ingredients and potential targets was performed using the AutoDock software. In total, 12 active compounds were selected from Ranunculi Ternati Radix. These active ingredients mainly act on the key targets of tuberculosis, including CASP3, CASP8, CASP9, BCL2, and BAX. KEGG results indicate that Ranunculi Ternati Radix may interfere with tuberculosis by regulating the apoptosis signaling pathway. The main components of Ranunculi Ternati Radix identified using molecular docking include stigmasta-4,6,8, vittadinoside, stigmasterol, stigmasterol glucoside, sitosterol acetate, and beta-sitosterol. These components were known to have obvious effects on BAX, CASP3, and CASP9. This study explored the active ingredients of Ranunculi Ternati Radix and corresponding potential targets when treating tuberculosis at the molecular level based on network pharmacology. Furthermore, the mechanism of action of Ranunculi Ternati Radix was verified.

Key words: network pharmacology, Ranunculi Ternati Radix, tuberculosis, signaling pathway, molecular docking

中图分类号:

R285

刘媛, 陈洁, 孙辉, 许苑南, 马志强, 刘向芳, 刘梦醒, 刘幸. 基于网络药理学的猫爪草治疗结核病作用机制研究[J]. 山东科学, 2021, 34(6): 51-61.

LIU Yuan, CHEN Jie, SUN Hui, XU Yuan-nan, MA Zhi-qiang, LIU Xiang-fang, LIU Meng-xing, LIU Xing. Study on the mechanism of Ranunculi Ternati Radix in the treatment of tuberculosis based on network pharmacology[J]. Shandong Science, 2021, 34(6): 51-61.

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编号	活性成分	OB/%	DL
MOL000242	7-O-methyleridictyol(7-O-甲基圣草酚)	56.56	0.27
MOL011328	stigmasta-4,6,8(豆甾-4,6,8)	48.02	0.77
MOL011330	vittadinoside_qt(维太菊苷)	43.83	0.76
MOL000449	stigmasterol(豆甾醇)	43.83	0.76
MOL006772	poriferasterolmonoglucoside_qt(豆甾醇葡萄糖苷)	43.83	0.76
MOL011319	truflex OBP(邻苯二甲酸正丁异辛酯)	43.74	0.24
MOL001494	mandenol(亚油酸乙酯)	42.00	0.19
MOL001973	sitosteryl acetate(谷甾醇乙酸酯)	40.39	0.85
MOL000593	cholesterol(胆固醇)	37.87	0.68
MOL005438	cmpesterol(菜油甾醇)	37.58	0.71
MOL000358	bate-sitosterol(β-谷甾醇)	36.91	0.75
MOL011312	(3R,8S,9S,10S,13R,17R)-17-((2S,5R)-5-ethyl-6-methylheptan-2-yl)-3,10,13-trimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenthrene	30.10	0.74

序号	靶点	Uniprot ID	序号	靶点	Uniprot ID	序号	靶点	Uniprot ID
1	ADH1C	P00326	15	CHRM3	P20309	29	OPRM1	P35372
2	ADRA1A	P35348	16	CHRM4	P08173	30	PGR	P06401
3	ADRA1B	P35368	17	CHRNA2	Q15822	31	PLAU	P00749
4	ADRA2A	P08913	18	CTRB1	P17538	32	PON1	P27169
5	ADRB1	P08588	19	GABRA1	P14867	33	PRKCA	P17612
6	ADRB2	P07550	20	JUN	P05412	34	PTGS1	P23219
7	AKR1B1	P15121	21	KCNH2	Q12809	35	PTGS2	P35354
8	BAX	Q07812	22	LTA4H	P09960	36	RXRA	P19793
9	BCL2	P10415	23	MAOA	P21397	37	SCN5A	Q14524
10	CASP3	P42574	24	MAP2	P11137	38	SLC6A2	P23975
11	CASP8	Q14790	25	NCOA1	Q15788	39	SLC6A3	Q01959
12	CASP9	P55211	26	NCOA2	Q15596	40	SLC6A4	P31645
13	CHRM1	P11229	27	NR3C2	P08235
14	CHRM2	P08172	28	MAOB	P27338

关键靶点	全称	Uniprot ID	度值
CASP3	Caspase-3	P42574	5
CASP8	Caspase-8	Q14790	5
CASP9	Caspase-9	P55211	5
BCL2	Apoptosis regulator Bcl-2	P10415	4
BAX	Apoptosis regulator BAX	Q07812	5
JUN	Transcription factor AP-1	P05412	4

信号通路	基因数	靶点	P值
乙肝	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	2.57×10^-7
凋亡	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	4.30×10^-7
癌症通路	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	3.57×10^-5
EB病毒感染	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	3.96×10^-5
麻疹	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	4.18×10^-5
TB	5	BAX、BCL2、CASP3、CASP8、CASP9	4.76×10^-5
HIV-1病毒感染	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	5.13×10^-5
p53信号通路	5	BAX、BCL2、CASP3、CASP8、CASP9	6.79×10^-5
单纯疱疹病毒感染	5	BAX、BCL2、CASP3、CASP8、CASP9	2.63×10^-2
沙门氏菌感染	5	JUN、BAX、BCL2、CASP3、CASP8	2.94×10^-2

活性成分	靶点
活性成分	CASP3	CASP8	CASP9	BCL2	BAX
7-O-Methyleridictyol	-7.5	-6.4	-6.3	-6.7	-7.0
Stigmasta-4,6,8	-7.6	-6.8	-8.4	-7.8	-9.0
vittadinoside_qt	-7.5	-7.1	-7.9	-7.0	-8.5
Stigmasterol	-7.7	-7.6	-8.5	-7.2	-8.7
poriferasterol monoglucoside_qt	-8.5	-7.2	-7.9	-8.2	-8.0
Truflex OBP	-5.3	-4.8	-4.5	-5.4	-5.8
Mandenol	-5.1	-4.4	-4.4	-5.6	-5.0
Sitosteryl acetate	-8.2	-6.8	-8.2	-7.6	-8.2
CLR	-7.3	-6.8	-8.0	-6.9	-8.5
cmpesterol	-6.9	-6.9	-8.4	-7.6	-8.8
bate-sitosterol	-6.9	-7.3	-8.4	-7.7	-8.3
(3R,8S,9S,10S,13R,17R)-17-((2S,5R)-5-ethyl-6- methylheptan-2-yl)-3,10,13-trimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenthrene	-7.1	-6.2	-7.1	-7.8	-8.2