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Research
Tingting Chen
Chongqing Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0089-9402
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Coronavirus Disease 2019 (COVID-19) respiratory disease rapidly caused a global pandemic and social and economic disruption. The combination of Traditional Chinese medicine (TCM) and Conventional Western medicine (CWM) is more effective for COVID-19 treatment. Moreover, TCM and CWM are important data source for developing new drug targets and promote strategies treat SARS-CoV-2 infections. However, many studies have analyzed the therapeutic mechanism of CWM or TCM alone for COVID-19, it is still unclear the interaction mechanism between TCM and CWM on COVID-19.
Methods
This paper integrates network pharmacology and GEO database to mine and identify COVID-19 molecular therapeutic targets, providing potential targets and new ideas for COVID-19 gene therapy and new drug development. It includes: 1) using TCMSP, TTD, PubChem and CTD databases to analyze drug interactions and associated phenotypes for SARS-CoV-2, to correlate drug and disease interaction mechanisms to screen key drug targets; 2) using GEO database to correlate differential genes and drug targets to screen potential antiviral gene therapy targets, to construct regulatory network and key points of SARS-CoV-2 therapeutic drugs; 3) using computer simulation of molecular docking to screen virus-related proteins for new drugs.
Results
Integrated analysis of network pharmacology discovered that baicalein, estrone and quercetin are the pivotal active ingredients in TCM and CWM. Combining drug target genes in pharmacology database and virus induced genes in GEO database, the result showed the core hub genes related to COVID-19: STAT1, IL1B, IL6, IL8, PTGS2 and NFKBIA, and these genes were significantly downregulated in A549 and NHBE cells by SARS-CoV-2 infection. Moreover, chemical interaction and molecular docking analysis of hub genes showed that folic acid might as be potential therapeutic drug for COVID-19 treatment, and SARS-CoV-2 nucleocapsid phosphoprotein was a potential drug target. The network of “drug-target-SARS-CoV-2 related genes” provide noval potential compounds and targets for further studies of SARS-CoV-2.
Conclusions
Integrated analysis of network pharmacology and big data mining provided noval potential compounds and targets for further studies of SARS-CoV-2. Our research implied folic acid and SARS-CoV-2 N as therapeutic target in TCM and CWM. Our research also suggests that targeting SARS-CoV-2 N protein is likely to be a common mechanism of TCM and CWM. On the one hand, the identification of pivotal genes provides a target for COVID-19 molecular therapy, on the other hand, it provides ideas for the analysis of interaction mechanism between virus and host.
Keywords
COVID-19, SARS-CoV-2, traditional Chinese medicine, big data mining, antivirus
Figure 1
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Figure 5
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This is a list of supplementary files associated with this preprint. Click to download.
- Figure.S1.tif
Fig.S1 Workflow of the present study. GEO: Gene Expression Omnibus; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: protein-protein interaction; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; CTD: Comparative Toxicogenomics Database; TTD: Therapeutic Target Database; HPA: Human Protein Atlas.
- Figure.S1.tif
Fig.S1 Workflow of the present study. GEO: Gene Expression Omnibus; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: protein-protein interaction; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; CTD: Comparative Toxicogenomics Database; TTD: Therapeutic Target Database; HPA: Human Protein Atlas.
- Figure.S2.tif
Fig.S2 GO and KEGG analysis of TCM and CWM target genes (A) GO analysis of target genes. (B) 3D structures of hub compounds.
- Figure.S2.tif
Fig.S2 GO and KEGG analysis of TCM and CWM target genes (A) GO analysis of target genes. (B) 3D structures of hub compounds.
- Figure.S3.tif
Fig.S3 Tissue expression profile of intersecting genes The NCBI database was used to analyze the tissue expression profile of intersecting genes in different human tissues, and MeV.5 was used for visualization. The red font is the up-regulated differential genes, the yellow box indicates that genes with low expression in the tissue, the blue box indicates the high expression of genes in kinds of tissues, the red box indicates that genes are highly expressed in liver tissues.
- Figure.S3.tif
Fig.S3 Tissue expression profile of intersecting genes The NCBI database was used to analyze the tissue expression profile of intersecting genes in different human tissues, and MeV.5 was used for visualization. The red font is the up-regulated differential genes, the yellow box indicates that genes with low expression in the tissue, the blue box indicates the high expression of genes in kinds of tissues, the red box indicates that genes are highly expressed in liver tissues.
- Figure.S4.tif
Fig.S4 Screening of key hub genes based on TTD, GEO and TCMSP datasets (A) Venn analysis of TCMSP and GEO datasets in Cov-group. (B) Venn analysis of TCMSP and GEO datasets in SARS-group. (C) The fold change of “TCMSP-GEO” joint genes after virus infection. (D) Venn analysis of genes in TTD, GEO and TCMSP datasets. (E) Venn analysis of chemical interaction.
- Figure.S4.tif
Fig.S4 Screening of key hub genes based on TTD, GEO and TCMSP datasets (A) Venn analysis of TCMSP and GEO datasets in Cov-group. (B) Venn analysis of TCMSP and GEO datasets in SARS-group. (C) The fold change of “TCMSP-GEO” joint genes after virus infection. (D) Venn analysis of genes in TTD, GEO and TCMSP datasets. (E) Venn analysis of chemical interaction.
- Figure.S5.tif
Fig.S5 Molecular docking of effective compounds to hub genes and SARS-CoV-2 related genes (A) The two-dimensional pattern that shows the hub genes of effective compounds on the associated proteins. (B) The two-dimensional pattern that shows the SARS-CoV-2 related genes of effective compounds on the associated proteins.
- Figure.S5.tif
Fig.S5 Molecular docking of effective compounds to hub genes and SARS-CoV-2 related genes (A) The two-dimensional pattern that shows the hub genes of effective compounds on the associated proteins. (B) The two-dimensional pattern that shows the SARS-CoV-2 related genes of effective compounds on the associated proteins.
- SupplementeryTables.docx
Table S1 Effective ingredient and target gene analysis of traditional Chinese medicine for COVID-19 Table S2 Statistical results of Venn analysis of effective compounds From user_list1 to user_list10 respectively indicated “Qingfei Detox Soup”, “Cold dampness lung syndrome”， “Damp heat syndrome”，“Damp-toxin depression lung syndrome”，“ Cold dampness syndrome”，“ Lung Closure Syndrome”，“ Trachea burnt certificate”，“ Internal and external withdrawal”，“ Pulmonary spleen Qi deficiency syndrome”，“ Qi-yin deficiency syndrome”.
- SupplementeryTables.docx
Table S1 Effective ingredient and target gene analysis of traditional Chinese medicine for COVID-19 Table S2 Statistical results of Venn analysis of effective compounds From user_list1 to user_list10 respectively indicated “Qingfei Detox Soup”, “Cold dampness lung syndrome”， “Damp heat syndrome”，“Damp-toxin depression lung syndrome”，“ Cold dampness syndrome”，“ Lung Closure Syndrome”，“ Trachea burnt certificate”，“ Internal and external withdrawal”，“ Pulmonary spleen Qi deficiency syndrome”，“ Qi-yin deficiency syndrome”.
- GraphicalAbstract.tif
Graphical Abstract The green line represents the results of pure network pharmacology analysis of traditional Chinese medicine, while the red line represents the hub compounds and their drug targets obtained from the integration of traditional Chinese medicine and Western medicine. The genes in the box are the pivotal genes between the differential genes induced by virus and the target genes of drug action. In addition, a new compound with potential effect on viral N protein was found by molecular docking. Network of “drug-target-SARS-CoV-2 related genes” was constructed through integrated analysis of pharmacology and GEO database, which provided a new molecular therapeutic target and drug screening direction for molecular of SARS-CoV-2.
- GraphicalAbstract.tif
Graphical Abstract The green line represents the results of pure network pharmacology analysis of traditional Chinese medicine, while the red line represents the hub compounds and their drug targets obtained from the integration of traditional Chinese medicine and Western medicine. The genes in the box are the pivotal genes between the differential genes induced by virus and the target genes of drug action. In addition, a new compound with potential effect on viral N protein was found by molecular docking. Network of “drug-target-SARS-CoV-2 related genes” was constructed through integrated analysis of pharmacology and GEO database, which provided a new molecular therapeutic target and drug screening direction for molecular of SARS-CoV-2.
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Tingting Chen
Chongqing Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0089-9402
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
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Prescreen
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CURRENT STATUS: Posted
Version 1
Posted 04 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Internal Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Coronavirus Disease 2019 (COVID-19) respiratory disease rapidly caused a global pandemic and social and economic disruption. The combination of Traditional Chinese medicine (TCM) and Conventional Western medicine (CWM) is more effective for COVID-19 treatment. Moreover, TCM and CWM are important data source for developing new drug targets and promote strategies treat SARS-CoV-2 infections. However, many studies have analyzed the therapeutic mechanism of CWM or TCM alone for COVID-19, it is still unclear the interaction mechanism between TCM and CWM on COVID-19.
Methods
This paper integrates network pharmacology and GEO database to mine and identify COVID-19 molecular therapeutic targets, providing potential targets and new ideas for COVID-19 gene therapy and new drug development. It includes: 1) using TCMSP, TTD, PubChem and CTD databases to analyze drug interactions and associated phenotypes for SARS-CoV-2, to correlate drug and disease interaction mechanisms to screen key drug targets; 2) using GEO database to correlate differential genes and drug targets to screen potential antiviral gene therapy targets, to construct regulatory network and key points of SARS-CoV-2 therapeutic drugs; 3) using computer simulation of molecular docking to screen virus-related proteins for new drugs.
Results
Integrated analysis of network pharmacology discovered that baicalein, estrone and quercetin are the pivotal active ingredients in TCM and CWM. Combining drug target genes in pharmacology database and virus induced genes in GEO database, the result showed the core hub genes related to COVID-19: STAT1, IL1B, IL6, IL8, PTGS2 and NFKBIA, and these genes were significantly downregulated in A549 and NHBE cells by SARS-CoV-2 infection. Moreover, chemical interaction and molecular docking analysis of hub genes showed that folic acid might as be potential therapeutic drug for COVID-19 treatment, and SARS-CoV-2 nucleocapsid phosphoprotein was a potential drug target. The network of “drug-target-SARS-CoV-2 related genes” provide noval potential compounds and targets for further studies of SARS-CoV-2.
Conclusions
Integrated analysis of network pharmacology and big data mining provided noval potential compounds and targets for further studies of SARS-CoV-2. Our research implied folic acid and SARS-CoV-2 N as therapeutic target in TCM and CWM. Our research also suggests that targeting SARS-CoV-2 N protein is likely to be a common mechanism of TCM and CWM. On the one hand, the identification of pivotal genes provides a target for COVID-19 molecular therapy, on the other hand, it provides ideas for the analysis of interaction mechanism between virus and host.
Figure 1
Figure 1
Figure 2
Figure 2
Figure 3
Figure 3
Figure 4
Figure 4
Figure 5
Figure 5
This is a list of supplementary files associated with this preprint. Click to download.
- Figure.S1.tif
Fig.S1 Workflow of the present study. GEO: Gene Expression Omnibus; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: protein-protein interaction; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; CTD: Comparative Toxicogenomics Database; TTD: Therapeutic Target Database; HPA: Human Protein Atlas.
- Figure.S1.tif
Fig.S1 Workflow of the present study. GEO: Gene Expression Omnibus; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: protein-protein interaction; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; CTD: Comparative Toxicogenomics Database; TTD: Therapeutic Target Database; HPA: Human Protein Atlas.
- Figure.S2.tif
Fig.S2 GO and KEGG analysis of TCM and CWM target genes (A) GO analysis of target genes. (B) 3D structures of hub compounds.
- Figure.S2.tif
Fig.S2 GO and KEGG analysis of TCM and CWM target genes (A) GO analysis of target genes. (B) 3D structures of hub compounds.
- Figure.S3.tif
Fig.S3 Tissue expression profile of intersecting genes The NCBI database was used to analyze the tissue expression profile of intersecting genes in different human tissues, and MeV.5 was used for visualization. The red font is the up-regulated differential genes, the yellow box indicates that genes with low expression in the tissue, the blue box indicates the high expression of genes in kinds of tissues, the red box indicates that genes are highly expressed in liver tissues.
- Figure.S3.tif
Fig.S3 Tissue expression profile of intersecting genes The NCBI database was used to analyze the tissue expression profile of intersecting genes in different human tissues, and MeV.5 was used for visualization. The red font is the up-regulated differential genes, the yellow box indicates that genes with low expression in the tissue, the blue box indicates the high expression of genes in kinds of tissues, the red box indicates that genes are highly expressed in liver tissues.
- Figure.S4.tif
Fig.S4 Screening of key hub genes based on TTD, GEO and TCMSP datasets (A) Venn analysis of TCMSP and GEO datasets in Cov-group. (B) Venn analysis of TCMSP and GEO datasets in SARS-group. (C) The fold change of “TCMSP-GEO” joint genes after virus infection. (D) Venn analysis of genes in TTD, GEO and TCMSP datasets. (E) Venn analysis of chemical interaction.
- Figure.S4.tif
Fig.S4 Screening of key hub genes based on TTD, GEO and TCMSP datasets (A) Venn analysis of TCMSP and GEO datasets in Cov-group. (B) Venn analysis of TCMSP and GEO datasets in SARS-group. (C) The fold change of “TCMSP-GEO” joint genes after virus infection. (D) Venn analysis of genes in TTD, GEO and TCMSP datasets. (E) Venn analysis of chemical interaction.
- Figure.S5.tif
Fig.S5 Molecular docking of effective compounds to hub genes and SARS-CoV-2 related genes (A) The two-dimensional pattern that shows the hub genes of effective compounds on the associated proteins. (B) The two-dimensional pattern that shows the SARS-CoV-2 related genes of effective compounds on the associated proteins.
- Figure.S5.tif
Fig.S5 Molecular docking of effective compounds to hub genes and SARS-CoV-2 related genes (A) The two-dimensional pattern that shows the hub genes of effective compounds on the associated proteins. (B) The two-dimensional pattern that shows the SARS-CoV-2 related genes of effective compounds on the associated proteins.
- SupplementeryTables.docx
Table S1 Effective ingredient and target gene analysis of traditional Chinese medicine for COVID-19 Table S2 Statistical results of Venn analysis of effective compounds From user_list1 to user_list10 respectively indicated “Qingfei Detox Soup”, “Cold dampness lung syndrome”， “Damp heat syndrome”，“Damp-toxin depression lung syndrome”，“ Cold dampness syndrome”，“ Lung Closure Syndrome”，“ Trachea burnt certificate”，“ Internal and external withdrawal”，“ Pulmonary spleen Qi deficiency syndrome”，“ Qi-yin deficiency syndrome”.
- SupplementeryTables.docx
Table S1 Effective ingredient and target gene analysis of traditional Chinese medicine for COVID-19 Table S2 Statistical results of Venn analysis of effective compounds From user_list1 to user_list10 respectively indicated “Qingfei Detox Soup”, “Cold dampness lung syndrome”， “Damp heat syndrome”，“Damp-toxin depression lung syndrome”，“ Cold dampness syndrome”，“ Lung Closure Syndrome”，“ Trachea burnt certificate”，“ Internal and external withdrawal”，“ Pulmonary spleen Qi deficiency syndrome”，“ Qi-yin deficiency syndrome”.
- GraphicalAbstract.tif
Graphical Abstract The green line represents the results of pure network pharmacology analysis of traditional Chinese medicine, while the red line represents the hub compounds and their drug targets obtained from the integration of traditional Chinese medicine and Western medicine. The genes in the box are the pivotal genes between the differential genes induced by virus and the target genes of drug action. In addition, a new compound with potential effect on viral N protein was found by molecular docking. Network of “drug-target-SARS-CoV-2 related genes” was constructed through integrated analysis of pharmacology and GEO database, which provided a new molecular therapeutic target and drug screening direction for molecular of SARS-CoV-2.
- GraphicalAbstract.tif
Graphical Abstract The green line represents the results of pure network pharmacology analysis of traditional Chinese medicine, while the red line represents the hub compounds and their drug targets obtained from the integration of traditional Chinese medicine and Western medicine. The genes in the box are the pivotal genes between the differential genes induced by virus and the target genes of drug action. In addition, a new compound with potential effect on viral N protein was found by molecular docking. Network of “drug-target-SARS-CoV-2 related genes” was constructed through integrated analysis of pharmacology and GEO database, which provided a new molecular therapeutic target and drug screening direction for molecular of SARS-CoV-2.
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