基于网络药理学和分子对接探讨猫爪草治疗肺腺癌的作用机制

doi:10.3976/j.issn.1002-4026.2022.04.007

摘要/Abstract

摘要：

应用网络药理学和分子对接探讨猫爪草多成分、多靶点、多通路治疗肺腺癌的作用机制。根据口服利用度和类药性的分析条件,采用中药系统药理学数据库与分析平台数据库筛选猫爪草主要活性成分及作用靶点;疾病靶点在GeneCards和OMIM数据库中获得;利用R软件绘制维恩图,获得活性成分和疾病的交集靶点,利用STRING数据库构建蛋白质-蛋白质相互作用网络;利用Bioconductor数据库对预测靶点进行GO(Gene ontology)功能富集分析和KEGG(Kyoto encyclopedia of genes and genomes)信号通路分析。结果表明:筛选出猫爪草的10个潜在活性成分和40个作用靶点,其中有36个靶点与肺腺癌相关;主要活性成分为β-谷甾醇、豆甾醇等,这些活性成分作用于PTGS2、BCL2、BAX、CASP9、CASP3、RXRA等靶点,通过调控神经变性的途径-多种疾病、神经活性配体-受体相互作用、小细胞肺腺癌、细胞凋亡、多细胞凋亡、铂类耐药、p53信号传导途径、大肠癌等通路发挥抗肿瘤作用。对猫爪草的有效成分和潜在靶点进行预测,为药物的应用和开发提供了新思路。

关键词: 网络药理学, 猫爪草, 肺腺癌, 作用机制

Abstract:

To explore the mechanism of a multicomponent, multitarget, and multichannel treatment of lung adenocarcinoma by network pharmacology and molecular docking. According to the analysis conditions of oral availability and drug-like properties, the Traditional Chinese Medicine systems pharmacology database and analysis peatform was used to screen the main active ingredients and targets of Ranunculi Ternati Radix. The disease targets were obtained from the GeneCards and OMIM databases. Venn diagrams were plotted using R software to obtain the intersection targets of active ingredients and diseases, and protein-protein interaction networks were constructed using the STRING database. Gene onto logy(GO) enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway analysis of the predicted targets were performed using the Bioconductor database. The results revealed 10 potential active ingredients and 40 targets of Ranunculi Ternati Radix on screening; of which, 36 targets were related to lung adenocarcinoma. The main active ingredients are β-sitosterol and dousterol. These active ingredients act on PTGS2, BCL2, BAX, CASP9, CASP3, RXRA, and other targets. The anti-tumor effect is elaborated through the regulation of neurodegeneration (multiple diseases), neuroactive ligand-receptor interactions, small cell lung adenocarcinoma, apoptosis, multicell apoptosis, platinum resistance, p53 signaling pathway, and colorectal cancer. The prediction of the active components and potential targets of Ranunculi Ternati Radix provides new ideas and indications for the application and development of drugs.

Key words: network pharmacology, Ranunculi Ternati Radix, lung adenocarcinoma, mechanism of action

中图分类号:

R285

刘幸, 黄红丽, 张乐, 刘向芳, 张文林, 沈凌筠. 基于网络药理学和分子对接探讨猫爪草治疗肺腺癌的作用机制[J]. 山东科学, 2022, 35(4): 49-57.

LIU Xing, HUANG Hong-li, ZHANG Le, LIU Xiang-fang, ZHANG Wen-lin, SHEN Ling-jun. To explore the mechanism of Ranunculi Ternati Radix in the treatment of lung adenocarcinoma based on network pharmacology and molecular docking[J]. Shandong Science, 2022, 35(4): 49-57.

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参考文献 20

[1]	冯骁, 仓顺东. 中国肺癌筛查标准(T/CPMA 013—2020)解读[J]. 中华实用诊断与治疗杂志, 2021, 35(3):217-219.DOI: 10.13507/j.issn.1674-3474.2021.03.001. doi: 10.13507/j.issn.1674-3474.2021.03.001
[2]	CHEUNG C H Y, JUAN H F. Quantitative proteomics in lung cancer[J]. Journal of Biomedical Science, 2017, 24(1):37. DOI: 10.1186/s12929-017-0343-y. doi: 10.1186/s12929-017-0343-y
[3]	梁敏群, 张杰, 林建团, 等. 胸部低剂量螺旋CT扫描在肺癌高危人群筛查中的应用[J]. 现代诊断与治疗, 2017, 28(7):1312-1313. DOI: 10.3969/j.issn.1001-8174.2017.07.087. doi: 10.3969/j.issn.1001-8174.2017.07.087
[4]	冯艺萍, 郭丽雯, 潘慧文. 猫爪草粗多糖治疗自身免疫性甲状腺炎的实验研究[J]. 药学研究, 2018, 37(10):559-561. DOI: 10.13506/j.cnki.jpr.2018.10.001. doi: 10.13506/j.cnki.jpr.2018.10.001
[5]	国家药典委员会. 中华人民共和国药典2015年版一部[M]. 北京: 中国医药科技出版社, 2015:319-320.
[6]	闫浩利, 王雯丽, 罗峰, 等. 猫爪草的提取工艺、药理作用及临床研究进展[J]. 中医研究, 2020, 33(11):78-80. DOI: 10.3969/j.issn.1001-6910.2020.11.26. doi: 10.3969/j.issn.1001-6910.2020.11.26
[7]	世界中医药学会联合会. 网络药理学评价方法指南[J]. 世界中医药, 2021, 16(4):527-532. DOI: 10.3969/j.issn.1673-7202.2021.04.001. doi: 10.3969/j.issn.1673-7202.2021.04.001
[8]	吉米丽汗·司马依, 买买提明·努尔买买提, 艾尼瓦尔·吾买尔, 等. 基于ADME和“Lipinski规则”的金叶败毒颗粒辅助治疗新型冠状病毒肺炎的活性成分研究[J]. 天然产物研究与开发, 2020, 32(10):1629-1636. DOI: 10.16333/j.1001-6880.2020.10.001. doi: 10.16333/j.1001-6880.2020.10.001
[9]	徐森楠, 庄莉, 翟园园, 等. 基于网络药理学研究二至丸防治骨质疏松症的物质基础与作用机制[J]. 中国药学杂志, 2018, 53(22):1913-1920. DOI: 10.11669/cpj.2018.22.007. doi: 10.11669/cpj.2018.22.007
[10]	杨金伟, 张莹. 猫爪草提取部位及有效成分抗肿瘤作用的研究进展[J]. 药物评价研究, 2021, 44(2):446-451. DOI: 10.7501/j.issn.1674-6376.2021.02.030. doi: 10.7501/j.issn.1674-6376.2021.02.030
[11]	童晔玲, 任泽明, 陈璇, 等. 猫爪草总皂苷通过下调信号素4D表达抑制人非小细胞肺癌A549细胞增殖[J]. 中国药理学与毒理学杂志, 2020, 34(9):670-676. DOI: 10.3867/j.issn.1000-3002.2020.09.004. doi: 10.3867/j.issn.1000-3002.2020.09.004
[12]	王会敏, 何柯新, 尚陈宇, 等. 猫爪草多糖的理化性质及其对ANA-1细胞的免疫调节作用[J]. 热带医学杂志, 2018, 18(7):855-859. DOI: 10.3969/j.issn.1672-3619.2018.07.005. doi: 10.3969/j.issn.1672-3619.2018.07.005
[13]	SERHAN N, CENAC N, BASSO L, et al. Mas-related G protein-coupled receptors (Mrgprs) - Key regulators of neuroimmune interactions[J]. Neuroscience letters, 2021, 23(15):749-753. DOI: 10.1016/j.neulet.2021.135724. doi: 10.1016/j.neulet.2021.135724
[14]	JIANG Y H, ZHUO X, MAO C Q. G protein-coupled receptors in cancer stem cells[J]. Current pharmaceutical design, 2020, 26(17):1952-1963. DOI: 10.2174/1381612826666200305130009. doi: 10.2174/1381612826666200305130009
[15]	田州彤, 倪嘉平, 胡唯伟. 神经递质在肿瘤发生发展中的作用研究进展[J]. 中国药科大学学报, 2020, 51(4):502-508. DOI: 10.11665/j.issn.1000-5048.20200417. doi: 10.11665/j.issn.1000-5048.20200417
[16]	THOMPSON E G, SONTHEIMER H. Acetylcholine receptor activation as a modulator of glioblastoma invasion[J]. Cells, 2019, 8(10):1203. DOI: 10.3390/cells8101203. doi: 10.3390/cells8101203
[17]	林明珠, 赵岩, 蔡恩博, 等. β-谷甾醇对H22荷瘤小鼠体内抗肿瘤作用[J]. 中国公共卫生, 2017, 33(12):1797-1800. DOI: 10.11847/zgggws2017-33-12-31. doi: 10.11847/zgggws2017-33-12-31
[18]	LI K, YUAN D W, YAN R, et al. Stigmasterol exhibits potent antitumor effects in human gastric cancer cells mediated via inhibition of cell migration, cell cycle arrest, mitochondrial mediated apoptosis and inhibition of JAK/STAT signalling pathway[J]. Journal of BUON, 2018, 23(5):1420-1425.
[19]	CARTWRIGHT I M, LIU X J, ZHOU M, et al. Essential roles of Caspase-3 in facilitating Myc-induced genetic instability and carcinogenesis[EB/OL].[2021-03-02]. .
[20]	LÓPEZ-TRIGO N, AGUÍN N, CASTUERA I P et al. Association of CASP3 genetic polymorphisms rs1049216, rs2705897 and rs4647603 with the risk of prostate cancer in Galicia (NW Spain)[J]. Gene, 2018. 7(3):142-145. DOI: 10.1016/j.gene.2018.08.073. doi: 10.1016/j.gene.2018.08.073

编号	活性成分	OB/%	DL
MOL000242	7-O-Methyleridictyol(7-O-甲基圣草酚)	56.56	0.27
MOL011330	vittadinoside_qt(维太菊苷)	43.83	0.76
MOL000449	Stigmasterol(豆甾醇)	43.83	0.76
MOL006772	poriferasterol monoglucoside_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	CLR(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

序号	靶点基因	count值	序号	靶点基因	count值	序号	靶点基因	count值	序号	靶点基因	count值
1	ADRA1B	11	10	ADRB2	8	19	CASP9	6	28	CHRM3	3
2	CASP3	11	11	SLC6A2	8	20	CHRM1	6	29	NR3C2	3
3	JUN	11	12	MAP2	7	21	CHRM2	6	30	ADH1C	2
4	MAOA	11	13	PGR	7	22	OPRM1	6	31	AKR1B1	2
5	ADRA2A	10	14	PRKCA	7	23	BAX	5	32	LTA4H	2
6	ADRA1A	9	15	SLC6A3	7	24	NCOA1	5	33	PTGS1	2
7	MAOB	9	16	ADRB1	6	25	NCOA2	5	34	KCNH2	1
8	PTGS2	9	17	BCL2	6	26	PLAU	4	35	PON1	1
9	SLC6A4	9	18	CASP8	6	27	RXRA	4	36	SCN5A	1

配体名称	靶点基因(PDB ID)亲和能/(kJ·mol^-1)
配体名称	ADRA1B(6TKO)	CASP3(5IC4)	JUN(5T01)	MAOA(2Z5Y)
7-O-Methyleridictyol(7-O-甲基圣草酚)	-29.706	-34.727	-23.430	-22.594
vittadinoside_qt(维太菊苷)	-29.288	-36.401	-32.635	-23.430
Stigmasterol(豆甾醇)	-37.238	-38.074	-30.962	-33.054
poriferasterol monoglucoside_qt(豆甾醇葡萄糖苷)	-32.635	-33.890	-28.033	-25.941
Truflex OBP(邻苯二甲酸正丁异辛酯)	-26.778	-32.217	-25.522	-23.012
Mandenol(亚油酸乙酯)	-28.870	-30.962	-31.798	-21.338
Sitosteryl acetate(谷甾醇乙酸酯)	-33.054	-34.309	-26.359	-24.267
CLR(胆固醇)	-35.982	-30.125	-30.125	-25.941
cmpesterol(菜油甾醇)	-33.890	-31.380	-36.819	-28.033
bate-sitosterol(β-谷甾醇)	-33.472	-36.819	-37.656	-32.217