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Article(id=1201124486272738013, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0904, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1690214400000, receivedDateStr=2023-07-25, revisedDate=1698249600000, revisedDateStr=2023-10-26, acceptedDate=null, acceptedDateStr=null, onlineDate=1764299993341, onlineDateStr=2025-11-28, pubDate=1710172800000, pubDateStr=2024-03-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764299993341, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764299993341, creator=13701087609, updateTime=1764299993341, updator=13701087609, issue=Issue{id=1201124478286786612, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='3', pageStart='493', pageEnd='788', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764299991434, creator=13701087609, updateTime=1764300490467, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201126571420639892, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201126571420639893, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=633, endPage=642, ext={EN=ArticleExt(id=1201124487631692549, articleId=1201124486272738013, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Anti-COVID-19 mechanism of Anoectochilus roxburghii liquid based on network pharmacology and molecular docking, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Anoectochilus roxburghii liquid (spray, a hospital preparation of Wu Mengchao Hepatobiliary Hospital of Fujian Medical University) has shown a good clinical treatment effect during the COVID-19 pandemic, but its material basis and mechanism of action are still unclear. In this study, network pharmacology and molecular docking methods were used to predict the molecular mechanism of A. roxburghii liquid against COVID-19, and pharmacodynamic experiments in vitro were conducted to study the interaction between the current targets with clear preventive and therapeutic effects and the key components of A. roxburghii liquid. UPLC-MS and database were used to compare and analyze the active ingredients in the liquid, and 17 potential active ingredients with good drug-like properties were screened by in vivo pharmacokinetics process in SwissADME database. SwissTargetPrediction and GeneCards were searched to find 93 common targets. Cytoscape 3.8.2 software was used to construct the "component-target" network map, and the Metascape platform was used for gene function annotation and pathway enrichment analysis. It was found that the extract could regulate the positive response to external stimuli, inflammatory response, cytokine production and other biological processes by binding the active ingredients such as isorhamnetin, kaempferol, luteolin, quercetin and apigenin to the common targets (NOS3, MPO, MMP3, etc.), and play an anti-COVID-19 role. In the angiotensin-converting enzyme 2 (ACE2) activity inhibition assay, it was found that the stock solution of A. roxburghii liquid (for spray), and the supernatant after removing polysaccharides (mainly containing flavonoids) could to some extent inhibit the activity of ACE2. Crucially, in the experiment of 2019-nCOV-S pseudovirus infecting HEK-293T-ACE2 cells, we found that A. roxburghii liquid may exert anti-COVID-19 effects by blocking the binding of SARS-CoV-S protein to ACE2.

, correspAuthors=Dan JIA, Cheng-jian ZHENG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jin ZHU, Yan-bin WU, De-fu HUANG, Bing-ke BAI, Xu-hui HE, Dan JIA, Cheng-jian ZHENG), CN=ArticleExt(id=1201124490165052405, articleId=1201124486272738013, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于网络药理学与分子对接的金线莲液抗COVID-19作用机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

金线莲液(喷雾用) 在COVID-19大流行期间表现出良好的临床治疗效果, 但其物质基础及作用机制尚不明确。本研究拟通过网络药理学及分子对接的方法预测金线莲液防治新冠的分子机制, 结合体外药效学实验对当前具有明确新冠防治效果的靶点与金线莲液重点成分的相互作用进行研究。首先运用UPLC-MS结合数据库比对分析金线莲液中活性成分, 经SwissADME数据库体内药代动力学过程筛选得到类药性较好的潜在活性成分17个, SwissTargetPrediction、GeneCards检索获得化合物疾病共有靶点93个。随后运用Cytoscape 3.8.2软件构建“成分-靶点”网络图, 以Metascape平台进行基因功能注释和富集通路分析, 发现金线莲液主要通过异鼠李素、山柰酚、木犀草素、槲皮素、芹菜素等活性成分与共有靶点(NOS3、MPO、MMP3等) 结合, 调节对外部刺激的积极反应、炎症反应、细胞因子产生等生物过程, 发挥抗COVID-19的作用。血管紧张素转换酶2 (angiotensin-converting enzyme 2, ACE2) 活性测定实验表明金线莲液(喷雾用) 原液及除去多糖后的上清液(主要为黄酮类成分) 对ACE2酶活性有一定的抑制作用。最后, 采用2019-nCOV-S蛋白假病毒感染HEK-293T-ACE2细胞, 发现金线莲液可能主要通过阻断新冠病毒S蛋白与ACE2的结合发挥抗病毒作用。

, correspAuthors=贾丹, 郑承剑, authorNote=null, correspAuthorsNote=
*贾丹, E-mail: ;
郑承剑, Tel: 86-21-81871358, E-mail:
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#共同第一作者.

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Faculty of Pharmacy, Naval Medical University, Shanghai 200433, China
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State Key Laboratory of Dao-di Herbs, Beijng 100700, China), AuthorCompanyExt(id=1201124491972796480, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, companyId=1201124491951824956, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=4.道地药材国家重点实验室, 北京 100700)])], figs=[ArticleFig(id=1201124497249231213, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=TRPbkWg6sp4LUxuI0fQE4A==, figureFileBig=6SKvNDpv1Kj7EIYWyWzZxA==, tableContent=null), ArticleFig(id=1201124497375060341, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Figure 1, caption= Interaction network of ingredients and target genes of <i>Anoectochilus roxburghii</i> liquid , figureFileSmall=TRPbkWg6sp4LUxuI0fQE4A==, figureFileBig=6SKvNDpv1Kj7EIYWyWzZxA==, tableContent=null), ArticleFig(id=1201124497572192644, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=FgSEXKVMgC/J8xN+MKI12g==, figureFileBig=OhjYzIE43XrlvN1xKRSR0A==, tableContent=null), ArticleFig(id=1201124497664467334, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Figure 2, caption= GO enrichment analysis of key targets of <i>Anoectochilus roxburghii</i> liquid for COVID-treatment (A) and KEGG signaling pathways enrichment analysis bubble chart of <i>Anoectochilus roxburghii</i> liquid for COVID-treatment (B) , figureFileSmall=FgSEXKVMgC/J8xN+MKI12g==, figureFileBig=OhjYzIE43XrlvN1xKRSR0A==, tableContent=null), ArticleFig(id=1201124497790296462, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=MoCWGdZROSmlsCGzg61Fig==, figureFileBig=QslVvssvYwZQSFTopkG41A==, tableContent=null), ArticleFig(id=1201124497937097112, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Figure 3, caption= Heat map of the docking binding energy of active ingredients with key targets (A) and the docking binding energy of active ingredients with key targets for COVID-2019 (B) , figureFileSmall=MoCWGdZROSmlsCGzg61Fig==, figureFileBig=QslVvssvYwZQSFTopkG41A==, tableContent=null), ArticleFig(id=1201124498054537631, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=VJCI5LyKS1jc20YwrxZkVA==, figureFileBig=XyqnyOOG0b2AJ1s3gb1CUQ==, tableContent=null), ArticleFig(id=1201124498222309796, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Figure 4, caption= Molecular docking of MMP3-luteolin (A), MMP3-quercetin (B), MPO-isorhamnetin (C), MPO-kaempferol (D), NOS3-apigenin (E), and NOS3-quercetin (F) , figureFileSmall=VJCI5LyKS1jc20YwrxZkVA==, figureFileBig=XyqnyOOG0b2AJ1s3gb1CUQ==, tableContent=null), ArticleFig(id=1201124498343944617, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=uV6JlWZuoNV0IZCfYP7QKw==, figureFileBig=APmuii8A2NmFfO1MMYh8Uw==, tableContent=null), ArticleFig(id=1201124498469773746, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Figure 5, caption= Inhibition of ACE2 activity (A) and molecular docking of luteolin and quercetin to ACE2 (B). ARL: <i>Anoectochilus roxburghii</i> liquid; PEARL: Polysaccharide extraction of <i>Anoectochilus roxburghii</i> liquid; CPEARL: Concentrated polysaccharide extraction of <i>Anoectochilus roxburghii</i> liquid; SARL: Supernatant of <i>Anoectochilus roxburghii</i> liquid; CSARL: Concentrated supernatant of <i>Anoectochilus roxburghii</i> liquid. <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=uV6JlWZuoNV0IZCfYP7QKw==, figureFileBig=APmuii8A2NmFfO1MMYh8Uw==, tableContent=null), ArticleFig(id=1201124498587214264, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=DDseCMtApLnfbcoklMWguA==, figureFileBig=1S7DmNSYcfst8EcMk6fQ/g==, tableContent=null), ArticleFig(id=1201124498721431997, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Figure 6, caption= Infection of COVID-19-spike protein pseudoviru with HEK-293T-ACE2 cell. A: Control; B: <i>Anoectochilus roxburghii</i> liquid; Scale bar: 100 μm , figureFileSmall=DDseCMtApLnfbcoklMWguA==, figureFileBig=1S7DmNSYcfst8EcMk6fQ/g==, tableContent=null), ArticleFig(id=1201124498855649729, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.FormulaCompoundClassificationTheoretical mass (m/z)Retention time/minPeak area
1 C6H6N2O Nicotinamide Alkaloid 123.055 8 0.75 175 834 136.016
2 C28H32O16 Isorhamnetin-3-O-neohesperosid* Flavonoids 625.176 8 5.55 96 062 483.793
3 C28H32O16 Narcissoside Flavonoids 625.176 8 5.55 96 062 483.793
4 C21H20O12 Hyperoside Flavonoids 465.103 3 5.08 47 853 655.447
5 C21H20O12 Isoquercitrin Flavonoids 465.103 3 5.08 47 853 655.447
6 C21H20O12 Quercetin-7-O-beta-D-glucopyranoside Flavonoids 465.103 3 5.08 47 853 655.447
7 C6H6O3 5-Hydroxymethylfurfural Aldehyde 127.039 5 1.98 40 657 683.314
8 C15H10O5 Apigenin Flavonoids 271.060 6 7.58 37 623 873.521
9 C7H6O2 4-Hydroxybenzaldehyde Aldehyde 123.044 6 3.73 32 495 217.177
10 C15H10O7 Quercetin Flavonoids 303.050 5 6.78 31 608 529.603
11 C16H12O7 Isorhamnetin Flavonoids 317.066 1 7.99 28 387 619.612
12 C22H22O12 Isorhamnetin 7-O-glucoside Flavonoids 479.118 9 5.72 24 938 679.992
13 C22H22O12 Isorhamnetin-3-O-beta-D-glucoside Flavonoids 479.118 9 5.72 24 938 679.992
14 C15H10O6 Luteolin Flavonoids 287.055 5 6.81 23 014 885.179
15 C9H10O3 Acetovanillone/apocynin Phenol 167.070 8 4.96 12 792 294.561
16 C9H8O3 p-Hydroxy-cinnamic acid Organic acids 165.055 1 4.37 12 552 628.526
17 C15H10O6 Kaempferol Flavonoids 287.055 5 7.71 9 056 013.128
18 C10H10O4 Ferulic acid Organic acids 195.065 7 4.92 7 948 071.827
19 C21H20O11 Luteolin-7-O-glucoside Flavonoids 449.108 4 5.14 6 584 913.682
20 C27H30O16 Rutin Flavonoids 611.161 2 4.94 6 025 519.264
21 C21H20O11 Quercitrin Flavonoids 449.108 4 5.73 4 816 696.133
22 C16H18O9 Chlorogenic acid Organic acids 355.102 9 3.43 2 107 121.727
23 C9H8O4 Caffeic acid Organic acids 181.050 1 3.69 2 074 399.038
24 C15H14O6 Epicatechin Flavonoids 291.086 8 3.96 894 546.032
25 C21H20O11 Isoorientin Flavonoids 449.108 4 4.53 349 859.148
26 C9H8O3 trans-3-Hydroxycinnamic acid Organic acids 165.055 1 5.3 212 170.466
27 C9H8O3 2-Hydroxycinnamic acid Organic acids 165.055 1 5.67 190 088.487
28 C21H20O11 Orientin Flavonoids 449.108 4 4.64 182 962.447
29 C30H48O3 Oleanolic acid* Organic acids 457.368 1 16.28 171 259.272
30 C30H48O3 Ursolic acid* Organic acids 457.368 1 16.28 171 259.272
31 C30H26O13 cis-Tiliroside Flavonoids 595.145 1 6.88 133 964.129
), ArticleFig(id=1201124498994061764, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Table 1, caption=

Compounds of Anoectochilus roxburghii liquid (spray) in the acetonitrile phase. Compounds marked with * are unique to the acetonitrile phase

, figureFileSmall=null, figureFileBig=null, tableContent=
No.FormulaCompoundClassificationTheoretical mass (m/z)Retention time/minPeak area
1 C6H6N2O Nicotinamide Alkaloid 123.055 8 0.75 175 834 136.016
2 C28H32O16 Isorhamnetin-3-O-neohesperosid* Flavonoids 625.176 8 5.55 96 062 483.793
3 C28H32O16 Narcissoside Flavonoids 625.176 8 5.55 96 062 483.793
4 C21H20O12 Hyperoside Flavonoids 465.103 3 5.08 47 853 655.447
5 C21H20O12 Isoquercitrin Flavonoids 465.103 3 5.08 47 853 655.447
6 C21H20O12 Quercetin-7-O-beta-D-glucopyranoside Flavonoids 465.103 3 5.08 47 853 655.447
7 C6H6O3 5-Hydroxymethylfurfural Aldehyde 127.039 5 1.98 40 657 683.314
8 C15H10O5 Apigenin Flavonoids 271.060 6 7.58 37 623 873.521
9 C7H6O2 4-Hydroxybenzaldehyde Aldehyde 123.044 6 3.73 32 495 217.177
10 C15H10O7 Quercetin Flavonoids 303.050 5 6.78 31 608 529.603
11 C16H12O7 Isorhamnetin Flavonoids 317.066 1 7.99 28 387 619.612
12 C22H22O12 Isorhamnetin 7-O-glucoside Flavonoids 479.118 9 5.72 24 938 679.992
13 C22H22O12 Isorhamnetin-3-O-beta-D-glucoside Flavonoids 479.118 9 5.72 24 938 679.992
14 C15H10O6 Luteolin Flavonoids 287.055 5 6.81 23 014 885.179
15 C9H10O3 Acetovanillone/apocynin Phenol 167.070 8 4.96 12 792 294.561
16 C9H8O3 p-Hydroxy-cinnamic acid Organic acids 165.055 1 4.37 12 552 628.526
17 C15H10O6 Kaempferol Flavonoids 287.055 5 7.71 9 056 013.128
18 C10H10O4 Ferulic acid Organic acids 195.065 7 4.92 7 948 071.827
19 C21H20O11 Luteolin-7-O-glucoside Flavonoids 449.108 4 5.14 6 584 913.682
20 C27H30O16 Rutin Flavonoids 611.161 2 4.94 6 025 519.264
21 C21H20O11 Quercitrin Flavonoids 449.108 4 5.73 4 816 696.133
22 C16H18O9 Chlorogenic acid Organic acids 355.102 9 3.43 2 107 121.727
23 C9H8O4 Caffeic acid Organic acids 181.050 1 3.69 2 074 399.038
24 C15H14O6 Epicatechin Flavonoids 291.086 8 3.96 894 546.032
25 C21H20O11 Isoorientin Flavonoids 449.108 4 4.53 349 859.148
26 C9H8O3 trans-3-Hydroxycinnamic acid Organic acids 165.055 1 5.3 212 170.466
27 C9H8O3 2-Hydroxycinnamic acid Organic acids 165.055 1 5.67 190 088.487
28 C21H20O11 Orientin Flavonoids 449.108 4 4.64 182 962.447
29 C30H48O3 Oleanolic acid* Organic acids 457.368 1 16.28 171 259.272
30 C30H48O3 Ursolic acid* Organic acids 457.368 1 16.28 171 259.272
31 C30H26O13 cis-Tiliroside Flavonoids 595.145 1 6.88 133 964.129
), ArticleFig(id=1201124499115696587, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.FormulaCompoundClassificationParent ions (m/z)Retention time/minPeak area
1 C28H32O16 Narcissoside Flavonoids 625.176 8 5.56 360 141 730.433
2 C6H6N2O Nicotinamide Alkaloid 123.055 8 0.77 322 069 111.273
3 C22H22O12 Isorhamnetin-3-O-beta-D-glucoside Flavonoids 479.118 9 5.56 125 694 608.876
4 C27H30O17 Quercetin-3-gentiobioside* Flavonoids 627.156 1 4.42 96 208 194.200
5 C27H30O17 Quercetin-3-O-sophoroside* Flavonoids 627.156 1 4.42 96 208 194.200
6 C21H20O12 Hyperoside Flavonoids 465.103 3 5.08 57 386 506.410
7 C21H20O12 Isoquercitrin Flavonoids 465.103 3 5.08 57 386 506.410
8 C21H20O12 Quercetin-7-O-beta-D-glucopyranoside Flavonoids 465.103 3 5.08 57 386 506.410
9 C27H30O16 Rutin Flavonoids 611.161 2 4.96 31 450 367.717
10 C6H6O3 5-Hydroxymethylfurfural Aldehyde 127.039 5 1.99 31 228 323.705
11 C9H8O3 trans-4-Hydroxycinnamic acid Organic acids 165.055 1 4.78 21 625 266.704
12 C16H18O9 Chlorogenic acid Organic acids 355.102 9 3.44 18 958 348.143
13 C21H20O11 Luteolin-7-O-glucoside Flavonoids 449.108 4 5.14 14 536 593.189
14 C21H20O11 Isoorientin Flavonoids 449.108 4 4.5 8 538 764.556
15 C21H20O11 Orientin Flavonoids 449.108 4 4.5 8 538 764.556
16 C9H8O4 Caffeic acid Organic acids 181.0501 3.59 6 531 741.290
17 C9H8O3 p-Hydroxy-cinnamic acid Organic acids 165.055 1 4.38 4 756 281.886
18 C7H6O2 4-Hydroxybenzaldehyde Aldehyde 123.044 6 3.74 4 021 347.971
19 C21H20O11 Quercitrin Flavonoids 449.108 4 5.72 3 308 932.566
20 C15H10O6 Luteolin Flavonoids 287.055 5 6.96 3 275 269.978
21 C10H10O4 Ferulic acid Organic acids 195.065 7 4.93 3 118 575.795
22 C7H6O5 Gallic acid* Organic acids 171.029 3 1.12 2 831 396.652
23 C15H10O5 Apigenin Flavonoids 271.060 6 7.61 2 684 751.734
24 C9H10O3 Acetovanillone/apocynin Phenol 167.070 8 4.96 2 413 349.760
25 C15H14O6 Epicatechin Flavonoids 291.086 8 3.96 1 319 571.235
26 C22H22O12 Isorhamnetin 7-O-glucoside Flavonoids 479.118 9 5.95 1 272 598.550
27 C30H26O13 cis-Tiliroside Flavonoids 595.145 1 6.85 1 195 472.445
28 C16H12O7 Isorhamnetin Flavonoids 317.066 1 7.99 1 137 304.267
29 C15H10O7 Quercetin Flavonoids 303.050 5 6.78 944 245.745
30 C15H10O6 Kaempferol Flavonoids 287.055 5 7.77 860 501.732
31 C9H8O3 2-Hydroxycinnamic acid Organic acids 165.055 1 5.75 766 017.535
32 C9H8O3 trans-3-Hydroxycinnamic acid Organic acids 165.055 1 5.29 482 355.837
), ArticleFig(id=1201124499241525716, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Table 2, caption=

Compounds of Anoectochilus roxburghii liquid (spray) in the water phase. Compounds marked with * are unique to the water phase

, figureFileSmall=null, figureFileBig=null, tableContent=
No.FormulaCompoundClassificationParent ions (m/z)Retention time/minPeak area
1 C28H32O16 Narcissoside Flavonoids 625.176 8 5.56 360 141 730.433
2 C6H6N2O Nicotinamide Alkaloid 123.055 8 0.77 322 069 111.273
3 C22H22O12 Isorhamnetin-3-O-beta-D-glucoside Flavonoids 479.118 9 5.56 125 694 608.876
4 C27H30O17 Quercetin-3-gentiobioside* Flavonoids 627.156 1 4.42 96 208 194.200
5 C27H30O17 Quercetin-3-O-sophoroside* Flavonoids 627.156 1 4.42 96 208 194.200
6 C21H20O12 Hyperoside Flavonoids 465.103 3 5.08 57 386 506.410
7 C21H20O12 Isoquercitrin Flavonoids 465.103 3 5.08 57 386 506.410
8 C21H20O12 Quercetin-7-O-beta-D-glucopyranoside Flavonoids 465.103 3 5.08 57 386 506.410
9 C27H30O16 Rutin Flavonoids 611.161 2 4.96 31 450 367.717
10 C6H6O3 5-Hydroxymethylfurfural Aldehyde 127.039 5 1.99 31 228 323.705
11 C9H8O3 trans-4-Hydroxycinnamic acid Organic acids 165.055 1 4.78 21 625 266.704
12 C16H18O9 Chlorogenic acid Organic acids 355.102 9 3.44 18 958 348.143
13 C21H20O11 Luteolin-7-O-glucoside Flavonoids 449.108 4 5.14 14 536 593.189
14 C21H20O11 Isoorientin Flavonoids 449.108 4 4.5 8 538 764.556
15 C21H20O11 Orientin Flavonoids 449.108 4 4.5 8 538 764.556
16 C9H8O4 Caffeic acid Organic acids 181.0501 3.59 6 531 741.290
17 C9H8O3 p-Hydroxy-cinnamic acid Organic acids 165.055 1 4.38 4 756 281.886
18 C7H6O2 4-Hydroxybenzaldehyde Aldehyde 123.044 6 3.74 4 021 347.971
19 C21H20O11 Quercitrin Flavonoids 449.108 4 5.72 3 308 932.566
20 C15H10O6 Luteolin Flavonoids 287.055 5 6.96 3 275 269.978
21 C10H10O4 Ferulic acid Organic acids 195.065 7 4.93 3 118 575.795
22 C7H6O5 Gallic acid* Organic acids 171.029 3 1.12 2 831 396.652
23 C15H10O5 Apigenin Flavonoids 271.060 6 7.61 2 684 751.734
24 C9H10O3 Acetovanillone/apocynin Phenol 167.070 8 4.96 2 413 349.760
25 C15H14O6 Epicatechin Flavonoids 291.086 8 3.96 1 319 571.235
26 C22H22O12 Isorhamnetin 7-O-glucoside Flavonoids 479.118 9 5.95 1 272 598.550
27 C30H26O13 cis-Tiliroside Flavonoids 595.145 1 6.85 1 195 472.445
28 C16H12O7 Isorhamnetin Flavonoids 317.066 1 7.99 1 137 304.267
29 C15H10O7 Quercetin Flavonoids 303.050 5 6.78 944 245.745
30 C15H10O6 Kaempferol Flavonoids 287.055 5 7.77 860 501.732
31 C9H8O3 2-Hydroxycinnamic acid Organic acids 165.055 1 5.75 766 017.535
32 C9H8O3 trans-3-Hydroxycinnamic acid Organic acids 165.055 1 5.29 482 355.837
), ArticleFig(id=1201124499358966232, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.CompoundGI absorptionBioavailability
1 Nicotinamide High 0.55
2 5-Hydroxymethylfurfural High 0.55
3 Apigenin High 0.55
4 4-Hydroxybenzaldehyde High 0.55
5 Quercetin High 0.55
6 Isorhamnetin High 0.55
7 Luteolin High 0.55
8 trans-4-Hydroxycinnamic acid High 0.85
9 Acetovanillone/apocynin High 0.55
10 p-Hydroxy-cinnamic acid High 0.85
11 Kaempferol High 0.55
12 trans-Ferulic acid High 0.85
13 Ferulic acid High 0.85
14 Gallic acid High 0.56
15 Caffeic acid High 0.56
16 Epicatechin High 0.55
17 trans-3-Hydroxycinnamic acid High 0.85
), ArticleFig(id=1201124499459629535, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124486272738013, language=CN, label=Table 3, caption=

In vivo pharmacokinetic process of potential active ingredients with good drug-like properties

, figureFileSmall=null, figureFileBig=null, tableContent=
No.CompoundGI absorptionBioavailability
1 Nicotinamide High 0.55
2 5-Hydroxymethylfurfural High 0.55
3 Apigenin High 0.55
4 4-Hydroxybenzaldehyde High 0.55
5 Quercetin High 0.55
6 Isorhamnetin High 0.55
7 Luteolin High 0.55
8 trans-4-Hydroxycinnamic acid High 0.85
9 Acetovanillone/apocynin High 0.55
10 p-Hydroxy-cinnamic acid High 0.85
11 Kaempferol High 0.55
12 trans-Ferulic acid High 0.85
13 Ferulic acid High 0.85
14 Gallic acid High 0.56
15 Caffeic acid High 0.56
16 Epicatechin High 0.55
17 trans-3-Hydroxycinnamic acid High 0.85
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基于网络药理学与分子对接的金线莲液抗COVID-19作用机制研究
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朱瑾 1, # , 吴岩斌 2, # , 黄德福 3 , 白冰珂 1 , 何旭辉 1 , 贾丹 1, * , 郑承剑 1, 4, *
药学学报 | 研究论文 2024,59(3): 633-642
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药学学报 | 研究论文 2024, 59(3): 633-642
基于网络药理学与分子对接的金线莲液抗COVID-19作用机制研究
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朱瑾1, #, 吴岩斌2, #, 黄德福3, 白冰珂1, 何旭辉1, 贾丹1, * , 郑承剑1, 4, *
作者信息
  • 1.海军军医大学药学系, 上海 200433
  • 2.福建中医药大学药学院, 福建 福州 350122
  • 3.福建医科大学孟超肝胆医院, 福建 福州 350025
  • 4.道地药材国家重点实验室, 北京 100700

通讯作者:

*贾丹, E-mail: ;
郑承剑, Tel: 86-21-81871358, E-mail:
Anti-COVID-19 mechanism of Anoectochilus roxburghii liquid based on network pharmacology and molecular docking
Jin ZHU1, Yan-bin WU2, De-fu HUANG3, Bing-ke BAI1, Xu-hui HE1, Dan JIA1, * , Cheng-jian ZHENG1, 4, *
Affiliations
  • 1. Faculty of Pharmacy, Naval Medical University, Shanghai 200433, China
  • 2. School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
  • 3. Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
  • 4. State Key Laboratory of Dao-di Herbs, Beijng 100700, China
出版时间: 2024-03-12 doi: 10.16438/j.0513-4870.2023-0904
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摘要
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金线莲液(喷雾用) 在COVID-19大流行期间表现出良好的临床治疗效果, 但其物质基础及作用机制尚不明确。本研究拟通过网络药理学及分子对接的方法预测金线莲液防治新冠的分子机制, 结合体外药效学实验对当前具有明确新冠防治效果的靶点与金线莲液重点成分的相互作用进行研究。首先运用UPLC-MS结合数据库比对分析金线莲液中活性成分, 经SwissADME数据库体内药代动力学过程筛选得到类药性较好的潜在活性成分17个, SwissTargetPrediction、GeneCards检索获得化合物疾病共有靶点93个。随后运用Cytoscape 3.8.2软件构建“成分-靶点”网络图, 以Metascape平台进行基因功能注释和富集通路分析, 发现金线莲液主要通过异鼠李素、山柰酚、木犀草素、槲皮素、芹菜素等活性成分与共有靶点(NOS3、MPO、MMP3等) 结合, 调节对外部刺激的积极反应、炎症反应、细胞因子产生等生物过程, 发挥抗COVID-19的作用。血管紧张素转换酶2 (angiotensin-converting enzyme 2, ACE2) 活性测定实验表明金线莲液(喷雾用) 原液及除去多糖后的上清液(主要为黄酮类成分) 对ACE2酶活性有一定的抑制作用。最后, 采用2019-nCOV-S蛋白假病毒感染HEK-293T-ACE2细胞, 发现金线莲液可能主要通过阻断新冠病毒S蛋白与ACE2的结合发挥抗病毒作用。

金线莲液(喷雾用)  /  COVID-19  /  网络药理学  /  分子靶点对接  /  作用机制

Anoectochilus roxburghii liquid (spray, a hospital preparation of Wu Mengchao Hepatobiliary Hospital of Fujian Medical University) has shown a good clinical treatment effect during the COVID-19 pandemic, but its material basis and mechanism of action are still unclear. In this study, network pharmacology and molecular docking methods were used to predict the molecular mechanism of A. roxburghii liquid against COVID-19, and pharmacodynamic experiments in vitro were conducted to study the interaction between the current targets with clear preventive and therapeutic effects and the key components of A. roxburghii liquid. UPLC-MS and database were used to compare and analyze the active ingredients in the liquid, and 17 potential active ingredients with good drug-like properties were screened by in vivo pharmacokinetics process in SwissADME database. SwissTargetPrediction and GeneCards were searched to find 93 common targets. Cytoscape 3.8.2 software was used to construct the "component-target" network map, and the Metascape platform was used for gene function annotation and pathway enrichment analysis. It was found that the extract could regulate the positive response to external stimuli, inflammatory response, cytokine production and other biological processes by binding the active ingredients such as isorhamnetin, kaempferol, luteolin, quercetin and apigenin to the common targets (NOS3, MPO, MMP3, etc.), and play an anti-COVID-19 role. In the angiotensin-converting enzyme 2 (ACE2) activity inhibition assay, it was found that the stock solution of A. roxburghii liquid (for spray), and the supernatant after removing polysaccharides (mainly containing flavonoids) could to some extent inhibit the activity of ACE2. Crucially, in the experiment of 2019-nCOV-S pseudovirus infecting HEK-293T-ACE2 cells, we found that A. roxburghii liquid may exert anti-COVID-19 effects by blocking the binding of SARS-CoV-S protein to ACE2.

Anoectochilus roxburghii liquid (for spray)  /  COVID-19  /  network pharmacology  /  molecular docking  /  mechanism
朱瑾, 吴岩斌, 黄德福, 白冰珂, 何旭辉, 贾丹, 郑承剑. 基于网络药理学与分子对接的金线莲液抗COVID-19作用机制研究. 药学学报, 2024 , 59 (3) : 633 -642 . DOI: 10.16438/j.0513-4870.2023-0904
Jin ZHU, Yan-bin WU, De-fu HUANG, Bing-ke BAI, Xu-hui HE, Dan JIA, Cheng-jian ZHENG. Anti-COVID-19 mechanism of Anoectochilus roxburghii liquid based on network pharmacology and molecular docking[J]. Acta Pharmaceutica Sinica, 2024 , 59 (3) : 633 -642 . DOI: 10.16438/j.0513-4870.2023-0904
正文
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自2019年新型冠状病毒(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) 席卷全球引起COVID-19大流行, 截至2023年12月20日, 根据世界卫生组织发布数据已有确诊病例7.7亿, 并造成超698万人死亡(https://www.who.int/emergencies/diseases/novel-coronavirus-2019)。中医药治疗疫病有悠久的历史, 在新冠肺炎的防治中发挥着其独特的作用。2020年, 中华人民共和国国家卫生健康委员会将中医药列为治疗新冠肺炎患者的推荐治疗方案。目前, 具有抗新冠治疗前景的主要包括单体活性成分(如黄芩苷、槲皮素、灯盏花素、粉防己碱)、粗提物(如黄芩提取物、大蒜提取物) 及复方(如连花清瘟胶囊、宣肺败毒散、清肺排毒汤) 等[1, 2]。
金线莲液(喷雾用, 福建医科大学吴孟超肝胆医院院内制剂), 是以兰科金线兰属植物金线兰Anoectochilus roxburghii (Wall.) Lindl.鲜草汁制成的液体制剂, 主要用于治疗乙型肝炎、儿童手足口病、小儿抽动-秽语综合征等[3-5]。在《福建省中医药防治新型冠状病毒肺炎专家共识(2022年12月普及版)》里, 被推荐为中医外用方案, 表现出良好的临床治疗效果。与对照组相比, 在基础治疗上加入金线莲液喷咽喉部的患者, 咽痛消失时间、咳嗽缓解时间、核酸转阴时间均明显缩短, 第10~14天的核酸转阴率显著提高[6]。金线莲中活性成分主要包括黄酮、多糖、有机酸、挥发油、甾体及生物碱等[7]。槲皮素被报道能够通过抑制丙型肝炎病毒(hepatitis C virus, HCV) RNA依赖性RNA聚合酶产生抗病毒作用[8]。金线莲苷(kinsenoside) 有良好的药理学活性, 能够抑制NF-κB的核易位及其转录活性, 同时增加细胞因子信号传导3抑制因子的水平, 导致白细胞介素-1β (interleukin-1β, IL-1β)、肿瘤坏死因子-α (tumour necrosis factor-α, TNF-α)、一氧化氮(nitric oxide, NO)、单核细胞趋化蛋白-1 (monocyte chemoattractant protein-1, MCP-1) 和巨噬细胞迁移抑制因子的表达减少, 以及白细胞介素-10 (interleukin-10, IL-10) 的含量升高, 显示出缓解细胞因子风暴的潜力[9]。同时, 金线莲苷抑制多种炎症信号通路与氧化应激, 因此还具有保肝、血管保护、降血糖、免疫调节、抑制感染等作用[10]。在现有的报道中, 尚无金线莲液抗COVID-19有效成分和作用机制研究。因此, 本课题拟分析金线莲液化学成分, 并进一步探究其作用机制。
网络药理学是一种在生物信息学、网络科学、高通量组学、靶向药理学等多学科综合基础上, 通过算法和实验相结合, 构建“成分-靶标-通路”相互作用关系, 探寻药效物质基础、作用机制的方法[11], 包括基于网络的疾病基因预测、药物靶点和药物功能预测、疾病特异性网络构建、中草药网络构建、药物-基因-疾病共模分析等一系列方法[12-15]。对于成分作用复杂的中草药, 天然具有系统性、整体性的网络药理学方法, 能够更好地体现中草药多成分、多靶点、复杂机制的特点, 同时网络药理学的预测性特点能够高效益地为研究人员提供研究思路, 筛选主要活性物质和重点靶标, 拓展新药开发和疾病治疗方法[16]。分子靶点对接通过研究小分子配体与受体生物大分子相互作用, 预测其结合模式和亲和力, 分子对接方法在不良反应预测、药物再利用、先导化合物发现、新药设计中发挥着重要的作用[17]。将潜在活性物质与疾病治疗靶点进行虚拟对接, 根据对接结果寻找与靶标蛋白有特异性相互作用的候选化合物, 提示药物可能的作用机制, 最后采用实验的方法进行生物活性检测。因此, 本研究希望利用网络药理学和分子靶点虚拟对接的方法, 构建金线莲抗COVID-19的“成分-靶点-通路”作用网络, 为其临床应用提供科学依据。
材料与方法
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细胞与假病毒  血管紧张素转换酶2 (angiotensin-converting enzyme 2, ACE2) 过表达的3FLAG-HEK293T稳定细胞株购自苏州复百澳生物科技有限公司(FBC2591)、2019-nCOV-S蛋白假病毒购自上海源叶生物科技有限公司(11906ES50)。
药品与试剂  金线莲液(福建医科大学孟超肝胆医院制剂, 20220911); ACE2抑制剂筛选试剂盒(碧云天生物技术有限公司, P0320); 槲皮素(纯度≥ 97%, 117-39-5)、异鼠李素(纯度≥ 98%, 480-19-3), 上海源叶生物科技有限公司; 山柰酚(纯度≥ 98%, 520-18-3)、木犀草素(纯度≥ 98%, 491-70-3)、芹菜素(纯度≥ 98.5%, 520-36-5), 上海毕得医药科技股份有限公司; 乙腈(01111812)、DMSO (P2154517), Damas-beta公司; 甲酸(江苏强盛功能更化学股份有限公司, 20130701); 乙酸铵(上海麦克林生化科技有限公司, C14460420); 超纯水(青岛聚创公司FST-Ⅱ-10/20纯水机制备)。
仪器  超高效液相色谱仪、Orbitrap高分辨质谱仪、96孔黑板(265301), Thermo Fisher Scientific公司; BEH C18色谱柱(2.1 mm × 100 mm, 1.7 μm, Waters公司); SpectraMax M5多功能酶标仪(Molecular Devices美谷子分子仪器有限公司); DM IL LED倒置荧光显微镜(徕卡显微系统公司); Mettler AE分析天平(梅特勒托利多科技有限公司)。
金线莲液成分分析
样品制备  取金线莲液4 mL与6 mL乙腈混合, 涡旋混合均匀, 放入-30 ℃冰箱经冷冻诱导液液萃取, 待相分离后, 分别取上层乙腈层和下层水层进行分析。
液相色谱条件BEH C18色谱柱(100 mm ×2.1 mm, 1.7 μm); 柱温50 ℃; 进样量5 μL; 流速0.45 mL·min-1; 正离子模式: 流动相(A) 为0.1%甲酸水溶液, 流动相(B) 为0.1%甲酸乙腈溶液; 负离子模式: 流动相(A) 为5 mmol·L-1乙酸铵水溶液, 流动相(B) 为5 mmol·L-1乙酸铵乙腈溶液; 流动相梯度洗脱程序: 0~20 min, 98% A; 20~24 min, 1% A; 25~30 min, 98% A。
质谱条件  离子源: 电喷雾离子源(ESI), 正、负离子模式, 喷雾电压为3 800 V (ESI+), 3 000 V (ESI-); 毛细管温度325 ℃; 离子源温度400 ℃; 簇裂解电压60 V; 鞘气体积流量40 L·min-1, 辅助气体积流量10 L·min-1, 尾气体积流量0; 归一化碰撞能量: 低能量10%, 中能量35%, 高能量55%; 采集范围50~1 000 m/z。
金线兰属化学成分数据库构建  对已有文献报道的金线兰属化学成分进行搜索整理, 构建包括化合物名、分子式、分子量、CAS号、植物归属等内容的金线兰属化学成分数据库。数据库涉及金线莲(金线兰)、台湾银线兰、兴仁金线兰、滇越金线兰、恒春银线兰等金线兰属植物化学成分, 共收录化学成分210个, 包括黄酮及其苷类55个, 其他苷类27个, 挥发油类49个, 有机酸类17个, 三萜类15个, 核苷类13个, 生物碱类4个, 以及其他酯类、酚类等化合物。
质谱结果化合物鉴定方法  以质谱结果准分子离子峰推断出化合物分子式, 依据分子式及二级质谱图等信息与mzCloud数据库化合物信息进行比对, 鉴定出UPLC-MS分析结果主要色谱峰对应化合物。将质谱鉴定结果与自建金线兰属化学成分数据库比对, 最终获得金线莲液中潜在活性成分。
网络药理学分析及分子对接
“成分-靶点”网络构建  将通过液-质联用方法分析得到的金线莲液中活性成分输入PubChem数据库(https://pubchem.ncbi.nlm.nih.gov/) 下载结构文件, 将化合物结构文件导入SwissADME数据库(http://www.swissadme.ch/) 查询其体内药代动力学特性, 筛选肠吸收(GI absorption) 高、类药性(druglikeness) 良好的化合物。将经药代动力学筛选得到的化合物结构文件导入SwissTargetPrediction数据库(http://www.swisstargetprediction.ch/), 设置靶点选择概率(probability) > 0, 获取化合物作用靶点。在GeneCards (https://www.genecards.org/) 数据库将物种设置为“Homo sapiens”, 以“COVID-19”为关键词检索新型冠状病毒肺炎相关靶点。利用UniProt数据库(https://www.uniprot.org/) 物种限定为human, 将获取的疾病靶点和化合物作用靶点转化为对应基因, 通过Venny 2.1作图工具(https://bioinfogp.cnb.csic.es/tools/venny/) 取交集靶点。根据预测的金线莲活性成分及作用靶点, 运用Cytoscape 3.8.2软件构建“成分-靶点”网络图, 计算节点值并调整节点大小。
蛋白质相互作用(protein-protein interaction, PPI) 网络构建  将化合物疾病交集靶点输入String数据库(https://cn.string-db.org/) 初步构建蛋白质相互作用网络, 运用Cytoscape 3.8.2软件计算PPI网络degree值, 并根据degree值进行筛选和调整。
基因功能注释和富集通路分析  将化合物疾病交集靶点录入Metascape平台, 设置物种为人(H. sapiens), P < 0.01, 分别从生物过程(biological processes, BP)、细胞成分(cellular components, CC)、分子功能(molecular functions, MF) 3方面进行基因本体(gene ontology, GO) 富集分析及京都基因与基因组百科全书数据库(kyoto encyclopedia of genes and genomes, KEGG) 富集分析。
分子靶点虚拟对接  将筛选出的关键活性成分sdf格式结构文件导入ChemBio3D Ultra 14.0软件转化为mol2格式文件。利用RCSB PDB数据库(https://www.rcsb.org/) 检索并下载通过PPI网络筛选出的核心靶点蛋白及新冠肺炎治疗热门靶点蛋白ACE2、新冠病毒S蛋白、跨膜丝氨酸蛋白酶2 (transmembrane serine protease-2, TMPRSS2)、组织蛋白酶L (cathepsin L, CTSL)、RdRp、主要蛋白酶(main protease, Mpro)、木瓜蛋白酶样蛋白酶(papain-like protease, PLpro) 等3D结构, 导入PyMOL2.4.1软件进行脱水、配体分离、加氢、电荷计算。使用AutoDock Vina进行批量分子对接, 使用AutoDock Tools进行精准对接, 并用PyMOLACE2软件绘制结合模式图。
活性抑制实验  阳性药对照品溶液配制: 阳性药品储配液MLN-4760 (0.5 mmol·L-1, IC50约7.5 nmol·L-1) 以assay buffer∶DMSO (1∶4, v/v) 作为溶剂稀释为0.2 µmol·L-1, 终浓度为10 nmol·L-1。样品溶液配制: 标准品以DMSO配制为10 mmol·L-1母液, 后以assay buffer∶DMSO (1∶4, v/v)作为溶剂稀释至约2 mmol·L-1, 终浓度为100 µmol·L-1。多糖与上清浓缩液: 取金线莲液10 mL, 浓缩至2 mL, 边搅拌缓慢加入95%乙醇使最终乙醇浓度达到80%, 放入4 ℃冰箱24 h, 离心, 得粗多糖沉淀, 用80%乙醇清洗3次, 干燥, 分别加入10或2 mL双蒸水配成多糖原液及多糖浓缩液; 上清液60 ℃旋干, 分别加入10或2 mL双蒸水配成上清原液及上清浓缩液。使用多功能酶标仪测量样品孔荧光值, 激发波长325 nm, 发射波长393 nm, 计算抑制率。对抑制率进行统计学分析, 计算各样品抑制率平均值及P值。
细胞实验  实验前一天, 将待感染HEK-293T-ACE2细胞接种于96孔细胞培养板中, 每孔接种量约为1×104个细胞。将病毒、药品、新鲜培养液配制为100 μL预混液, 加入96孔板, 病毒感染24 h后更换新鲜培养基继续培养, 细胞感染假病毒换液后24~48 h, 荧光显微镜观察GFP荧光。
统计学分析  实验数据通过GraphPad Prism 8.0和Excel 2010软件统计分析。多组间比较采用单因素方差分析, 两组间数据采用独立样本t检验。P < 0.05被认为组间差异具有统计学意义。
结果
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1 金线莲液成分分析
本研究采用液-质联用方法获得金线莲液化学成分, 将结果数据与自建金线兰属化学成分数据库比对, 得到金线莲液中化学成分。最终鉴定得到化合物35个(表 1、2), 其中乙腈相鉴定得化合物31个, 水相32个, 28个化合物两相均有。结果显示, 金线莲液中成分以黄酮类为主, 同时有少量有机酸类化合物及其他成分。
2 网络药理学分析及分子对接
2.1 活性成分和靶点筛选
将液-质联用分析鉴定得到的31个化合物进行体内药代动力学和类药性筛选, 得到GI absorption为high、druglikeness评分(Lipinski、Ghose、Veber、Egan、Muegge) 3个及以上为Yes的化合物17个(表 3)。使用GeneCards数据库获取COVID-19疾病靶点6 050个, 根据相关性评分(relevance score) 筛选高于中位数的条目, 得到靶点3 046个。对17个潜在活性成分作用靶点与疾病靶点取交集, 得到可作为金线莲液中化学成分治疗COVID-19的靶点93个。
2.2 “成分-靶点”网络构建
将筛选得到的17个活性成分与93个靶点导入Cytoscape 3.8.2软件, 构建金线莲液中活性成分治疗COVID-19的“成分-靶点”网络图(图 1), 共包含110个节点、300条边, 蓝色节点为化合物, 黄色节点代表潜在的疾病治疗靶点, 以节点大小表示degree值大小, 其中degree值排名靠前的活性成分为儿茶素、香草乙酮、芹菜素、木犀草素、5-羟甲基糠醛、4-羟基苯甲醛、山柰酚、异鼠李素、槲皮素, 这些可能是金线莲液发挥抗新冠作用的关键活性物质。
2.3 PPI网络构建和分析
本研究将金线莲化学成分与COVID-19疾病交集靶点输入String数据库初步构建PPI网络, 运用Cytoscape 3.8.2软件对PPI网络进行调整和分析, degree值排名靠前的靶点有AKT1、EGFR、TLR4、NOS3、RELA、STAT3、ACE等, 提示这些靶点可能是金线莲液中活性成分治疗新冠的潜在核心靶点。
2.4 基因功能注释和富集通路分析
通过Metascape平台录入93个化合物疾病共同靶点进行GO富集分析和KEGG富集分析, 获得GO富集结果460条, 其中BP富集结果271条、CC富集结果91条、MF富集结果98条, 以及KEGG富集结果177条。对GO富集分析3个项目中-lgP值排名前10的条目及KEGG富集分析排名前20的条目进行可视化, 将数据导入微生信在线作图工具, 分别绘制条形图和气泡图(图 2)。
GO富集结果显示, 金线莲液中活性成分抗新冠主要通过调节对外部刺激的积极反应、炎症反应、细胞因子产生等生物过程发挥作用, 对细胞的作用部位主要为囊泡腔、分泌颗粒腔等, 分子功能主要涉及蛋白激酶活性、磷酸转移酶活性、丝氨酸型肽酶活性等。KEGG富集结果则包括COVID-19通路、人巨噬细胞病毒感染通路、趋化因子信号通路、Toll样受体信号通路等, 同时还提示金线莲可能用于治疗癌症、丙型肝炎、麻疹、弓形虫锥虫感染等疾病。
2.5 分子靶点虚拟对接
将经体内药代动力学过程筛选的潜在活性成分及通过PPI网络筛选的19个潜在核心靶点进行分子对接, 绘制热图呈现结合能高低(图 3A)。结果显示异鼠李素、山柰酚、木犀草素、槲皮素、芹菜素、儿茶素与NOS3、MPO、MMP3、EGFR等靶点有较好的结合能力。在现有文献报道中, 槲皮素等成分被报道与新冠热门靶点CTSL、ACE2等具有相互作用, 因此本研究对这些靶点进行虚拟对接作为实验的补充。异鼠李素、山柰酚、木犀草素、槲皮素、芹菜素、儿茶素6个成分在分子对接中与靶点具有良好的结合能力, 将该成分与新冠热门治疗靶点进行分子对接, 以结合能数据绘制热图(图 3B)。结果显示, 筛选出的6个潜在活性成分与SARS-CoV-2 S蛋白、ACE2、CTSL等靶点具有较好的结合能力。选取结合能较低的组合可视化分子-靶点结合模式图(图 4)。
3 体外药效学实验
3.1 ACE2活性抑制实验
以MLN-4760为阳性抑制剂, 进行ACE2抑制剂筛选。实验结果见图 5A, 金线莲液(喷雾用) 原液、多糖及除去多糖后的上清液(主要为黄酮类成分) 对ACE2酶活性有一定的抑制作用, 抑制率分别为32.78%、18.08%及39.40%, 其作用均弱于阳性抑制剂MLN-4760 (57.77%)。多糖浓缩液及上清浓缩液[5倍金线莲液(喷雾用) 制剂浓度] 可显著抑制ACE2酶活性, 对该制剂在临床的应用剂量具有重要参考意义。分析对接显示(图 5B), 抑制率较高的黄酮类成分木犀草素和槲皮素与ACE2具有适度的结合能力。
3.2 细胞实验
实验结果见图 6, 给予1 μg·μL-1金线莲液作用48 h后实验组细胞荧光显著低于对照组, 表明金线莲液在细胞实验中能够通过阻断S蛋白RBD结合域与ACE2的结合, 发挥抗病毒作用。
讨论
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由SARS-CoV-2引起的COVID-19世界性大流行对人类生命安全造成了巨大的损失, 在此期间中草药对疫情防治贡献了独特的力量。金线莲液是福建医科大学吴孟超肝胆医院院内制剂, 以兰科金线兰属植物金线莲Anoectochilus roxburghii (Wall.) Lindl.鲜草汁制成, 在疫情期间作为口腔喷雾使用, 显示出良好的临床使用潜力[6]。本研究采用超高效液相色谱-质谱联用的方法研究金线莲液中主要活性成分, 通过网络药理学和虚拟分子对接方法预测了金线莲液发挥防治新冠作用的机制。
大量研究表明, 黄酮和多糖为金线莲中的主要活性成分[7]。本研究分别考察了异鼠李素、山柰酚、木犀草素、槲皮素、芹菜素等黄酮类成分, 以及金线莲液(喷雾用) 原液、多糖和除去多糖后的上清液(主要为黄酮类成分) 分别对ACE2酶活性的影响, 结果表明金线莲液(喷雾用) 原液、多糖及除去多糖后的上清液(主要为黄酮类成分) 对ACE2酶活性有一定的抑制作用, 抑制率分别为32.78%、18.08%及39.40%, 其作用弱于阳性抑制剂MLN-4760 (57.77%)。研究表明, ACE2是SARS冠状病毒的RAS调节剂和核心受体, ACE2与SARS-CoV-2 S蛋白的相互作用介导SARS-CoV-2进入细胞[18]。同时, ACE2通过在人体中的酶和氨基酸转运功能促进生理稳态: ACE2对降低血压、保护心肌缺血、抑制血栓形成及动脉粥样硬化等心脏疾病具有积极的意义; 能抑制肿瘤细胞生长及血管生成、抑制炎症因子、改善高血糖症、降低纤维增生等[19]。多糖浓缩液及上清浓缩液[相当于金线莲液(喷雾用) 制剂浓度的5倍] 可显著抑制ACE2酶活性, 其可能潜在的心血管系统作用与用药剂量密切相关, 因此上述结果对该制剂在临床中用药剂量具有重要的指导意义。文献报道, 黄酮类化合物在新冠期间的抗病毒作用受到关注, 如黄芩苷[20, 21]等, 普遍认为黄酮类化合物能够抑制病毒蛋白酶、RNA聚合酶、病毒复制和降低传染性, 从而直接发挥抗病毒活性, 这些化合物还能有效调节干扰素、促炎细胞因子和亚细胞炎症途径间接治疗病毒性疾病[22]。网络药理学预测结果显示, 金线莲液主要作用于NOS3、MPO、MMP3等靶点, 在基因功能注释和富集通路分析中发现金线莲液通过调节对外部刺激的积极反应、炎症反应、细胞因子产生等生物过程, 最终达到防治COVID-19的目的。
文献[1]报道黄豆苷能够与SRBD和ACE2结合, 而在先前的研究中多采用单纯虚拟分子对接或考察结合的方式对其作用机制进行预测。ACE2的活性与ACE2/SARS-CoV-2 S的相互作用无必然联系。本研究采用2019-nCOV-S蛋白假病毒感染HEK-293T-ACE2细胞, 发现金线莲液可显著抑制病毒感染, 提示其可能主要通过阻断新冠病毒S蛋白与ACE2的结合发挥抗病毒作用。
作者贡献: 朱瑾负责文献调研、网络药理学分析、体外药效学实验、数据分析和文章撰写; 吴岩斌、何旭辉负责化学成分分析、数据收集和文章撰写; 黄德福负责药物制备和数据分析; 白冰珂负责体外药效学实验、数据收集; 贾丹、郑承剑负责实验设计、文章修改和指导审阅。
利益冲突: 本文作者均声明不存在利益冲突。
基金
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  • 国家自然科学基金资助项目(82174081)
  • 国家自然科学基金资助项目(82374118)
  • 国家自然科学基金资助项目(82004002)
  • 上海市浦江人才计划(21PJD082)
  • 中央本级重大增减支项目“名贵中药资源可持续利用能力建设项目”(2060302)
文献
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参考文献 引证文献
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2024年第59卷第3期
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doi: 10.16438/j.0513-4870.2023-0904
  • 接收时间：2023-07-25
  • 首发时间：2025-11-28
  • 出版时间：2024-03-12
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  • 收稿日期：2023-07-25
  • 修回日期：2023-10-26
基金
国家自然科学基金资助项目(82174081)
国家自然科学基金资助项目(82374118)
国家自然科学基金资助项目(82004002)
上海市浦江人才计划(21PJD082)
中央本级重大增减支项目“名贵中药资源可持续利用能力建设项目”(2060302)
作者信息
    1.海军军医大学药学系, 上海 200433
    2.福建中医药大学药学院, 福建 福州 350122
    3.福建医科大学孟超肝胆医院, 福建 福州 350025
    4.道地药材国家重点实验室, 北京 100700

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郑承剑, Tel: 86-21-81871358, E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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