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Exploring the bioactive compounds of Feiduqing formula for the prevention and management of COVID-19 through network pharmacology and molecular docking

Qin et al., Medical Data Mining, doi:10.53388/MDM202407003

Nov 2023

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Quercetin for COVID-19

24th treatment shown to reduce risk in July 2021, now with p = 0.0031 from 11 studies.

Lower risk for ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19early.org

In Silico study of components of Feiduqing finding that quercetin, among other compounds, has significant binding affinity to PTGS2, HSP90AA1, SARS-CoV-2 M^pro, and ACE2, suggesting that quercetin may have therapeutic potential for COVID-19. PTGS2 (prostaglandin-endoperoxide synthase 2), also known as COX-2, is an enzyme involved in prostaglandin biosynthesis and inflammation and is a target for anti-inflammatory drugs. HSP90AA1 is a heat shock protein that helps fold and stabilize proteins and has been shown to be important for replication of some RNA viruses.

68 preclinical studies support the efficacy of quercetin for COVID-19:

42 In Silico studies1-42

20 In Vitro studies2,12,16,18,22,39,43-56

6 In Vivo animal studies2,16,49,52,57,58

In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,6,7,19,21,22,27,35,36,38,39,59,60, M^proB,4,6,8,10,12,14,15,17,20,21,27,31,33-35,39,40,42,60,61, RNA-dependent RNA polymeraseC,6,29, PLproD,34,42, ACE2E,19,20,25,34,38,60, TMPRSS2F,19, helicaseG,26,31, endoribonucleaseH,36, NSP16/10I,3, cathepsin LJ,23, Wnt-3K,19, FZDL,19, LRP6M,19, ezrinN,37, ADRPO,35, NRP1P,38, EP300Q,13, PTGS2R,20, HSP90AA1S,13,20, matrix metalloproteinase 9T,28, IL-6U,18,32, IL-10V,18, VEGFAW,32, and RELAX,32 proteins. In Vitro studies demonstrate inhibition of the M^proB,12,43,48,56 protein, and inhibition of spike-ACE2 interactionY,44. In Vitro studies demonstrate efficacy in Calu-3Z,47, A549AA,18, HEK293-ACE2+AB,55, Huh-7AC,22, Caco-2AD,46, Vero E6AE,16,39,46, mTECAF,49, and RAW264.7AG,49 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAH,52, db/db miceAI,49,58, BALB/c miceAJ,57, and rats62. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice57, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages2, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity51.

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2. Xu et al., Quercetin inhibited LPS-induced cytokine storm by interacting with the AKT1-FoxO1 and Keap1-Nrf2 signaling pathway in macrophages, Scientific Reports, doi:10.1038/s41598-024-71569-y.nature.com, doi.org.

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16. El-Megharbel et al., Chemical and spectroscopic characterization of (Artemisinin/Quercetin/ Zinc) novel mixed ligand complex with assessment of its potent high antiviral activity against SARS-CoV-2 and antioxidant capacity against toxicity induced by acrylamide in male rats, PeerJ, doi:10.7717/peerj.15638.peerj.com, doi.org.

17. Akinwumi et al., Evaluation of therapeutic potentials of some bioactive compounds in selected African plants targeting main protease (Mpro) in SARS-CoV-2: a molecular docking study, Egyptian Journal of Medical Human Genetics, doi:10.1186/s43042-023-00456-4.springeropen.com, doi.org.

18. Yang et al., Active ingredient and mechanistic analysis of traditional Chinese medicine formulas for the prevention and treatment of COVID-19: Insights from bioinformatics and in vitro experiments, Medicine, doi:10.1097/MD.0000000000036238.lww.com, doi.org.

19. Chandran et al., Molecular docking analysis of quercetin with known CoVid-19 targets, Bioinformation, doi:10.6026/973206300191081.bioinformation.net, doi.org.

20. Qin et al., Exploring the bioactive compounds of Feiduqing formula for the prevention and management of COVID-19 through network pharmacology and molecular docking, Medical Data Mining, doi:10.53388/MDM202407003.tmrjournals.com, doi.org.

21. Moschovou et al., Exploring the Binding Effects of Natural Products and Antihypertensive Drugs on SARS-CoV-2: An In Silico Investigation of Main Protease and Spike Protein, International Journal of Molecular Sciences, doi:10.3390/ijms242115894.mdpi.com, doi.org.

22. Pan (B) et al., Quercetin: A promising drug candidate against the potential SARS-CoV-2-Spike mutants with high viral infectivity, Computational and Structural Biotechnology Journal, doi:10.1016/j.csbj.2023.10.029.sciencedirect.com, doi.org.

23. Ahmed et al., Evaluation of the Effect of Zinc, Quercetin, Bromelain and Vitamin C on COVID-19 Patients, International Journal of Diabetes Management, doi:10.61797/ijdm.v2i2.259.researchlakejournals.com, doi.org.

24. Thapa et al., In-silico Approach for Predicting the Inhibitory Effect of Home Remedies on Severe Acute Respiratory Syndrome Coronavirus-2, Makara Journal of Science, doi:10.7454/mss.v27i3.1609.ac.id, doi.org.

25. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

26. Singh (B) et al., Flavonoids as Potent Inhibitor of SARS-CoV-2 Nsp13 Helicase: Grid Based Docking Approach, Middle East Research Journal of Pharmaceutical Sciences, doi:10.36348/merjps.2023.v03i04.001.kspublisher.com, doi.org.

27. Mandal et al., In silico anti-viral assessment of phytoconstituents in a traditional (Siddha Medicine) polyherbal formulation – Targeting Mpro and pan-coronavirus post-fusion Spike protein, Journal of Traditional and Complementary Medicine, doi:10.1016/j.jtcme.2023.07.004.sciencedirect.com, doi.org.

28. Sai Ramesh et al., Computational analysis of the phytocompounds of Mimusops elengi against spike protein of SARS CoV2 – An Insilico model, International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2023.125553.sciencedirect.com, doi.org.

29. Corbo et al., Inhibitory potential of phytochemicals on five SARS-CoV-2 proteins: in silico evaluation of endemic plants of Bosnia and Herzegovina, Biotechnology & Biotechnological Equipment, doi:10.1080/13102818.2023.2222196.tandfonline.com, doi.org.

30. Azmi et al., Utilization of quercetin flavonoid compounds in onion (Allium cepa L.) as an inhibitor of SARS-CoV-2 spike protein against ACE2 receptors, 11th International Seminar on New Paradigm and Innovation on Natural Sciences and its Application, doi:10.1063/5.0140285.scitation.org, doi.org.

31. Alanzi et al., Structure-based virtual identification of natural inhibitors of SARS-CoV-2 and its Delta and Omicron variant proteins, Future Virology, doi:10.2217/fvl-2022-0184.futuremedicine.com, doi.org.

32. Yang (B) et al., In silico evidence implicating novel mechanisms of Prunella vulgaris L. as a potential botanical drug against COVID-19-associated acute kidney injury, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1188086.frontiersin.org, doi.org.

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34. Ibeh et al., Computational studies of potential antiviral compounds from some selected Nigerian medicinal plants against SARS-CoV-2 proteins, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2023.101230.sciencedirect.com, doi.org.

35. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

36. Alavi et al., Interaction of Epigallocatechin Gallate and Quercetin with Spike Glycoprotein (S-Glycoprotein) of SARS-CoV-2: In Silico Study, Biomedicines, doi:10.3390/biomedicines10123074.mdpi.com, doi.org.

37. Chellasamy et al., Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors, Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277.sciencedirect.com, doi.org.

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41. Sekiou et al., In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2, ChemRxiv, doi:10.26434/chemrxiv.12181404.v1.chemrxiv.org, doi.org.

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61. Sekiou (B) et al., In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2, ChemRxiv, doi:10.26434/chemrxiv.12181404.v1.chemrxiv.org, doi.org.

62. El-Megharbel (B) et al., Chemical and spectroscopic characterization of (Artemisinin/Quercetin/ Zinc) novel mixed ligand complex with assessment of its potent high antiviral activity against SARS-CoV-2 and antioxidant capacity against toxicity induced by acrylamide in male rats, PeerJ, doi:10.7717/peerj.15638.peerj.com, doi.org.

a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.

b. The main protease or M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.

c. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.

d. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.

e. The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.

f. Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.

g. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.

h. The endoribonuclease, also known as NendoU or nsp15, cleaves specific sequences in viral RNA which may help the virus evade detection by the host immune system. Inhibition may hinder the virus's ability to mask itself from the immune system, facilitating a stronger immune response.

i. The NSP16/10 complex consists of non-structural proteins 16 and 10, forming a 2'-O-methyltransferase that modifies the viral RNA cap structure. This modification helps the virus evade host immune detection by mimicking host mRNA, making NSP16/10 a promising antiviral target.

j. Cathepsin L is a host lysosomal cysteine protease that can prime the spike protein through an alternative pathway when TMPRSS2 is unavailable. Dual targeting of cathepsin L and TMPRSS2 may maximize disruption of alternative pathways for virus entry.

l. The frizzled (FZD) receptor is a host transmembrane receptor that binds Wnt ligands, initiating the Wnt signaling cascade. FZD serves as a co-receptor, along with ACE2, in some proposed mechanisms of SARS-CoV-2 infection. The virus may take advantage of this pathway as an alternative entry route.

m. Low-density lipoprotein receptor-related protein 6 is a cell surface co-receptor essential for Wnt signaling. LRP6 acts in tandem with FZD for signal transduction and has been discussed as a potential co-receptor for SARS-CoV-2 entry.

n. The ezrin protein links the cell membrane to the cytoskeleton (the cell's internal support structure) and plays a role in cell shape, movement, adhesion, and signaling. Drugs that occupy the same spot on ezrin where the viral spike protein would bind may hindering viral attachment, and drug binding could further stabilize ezrin, strengthening its potential natural capacity to impede viral fusion and entry.

o. The Adipocyte Differentiation-Related Protein (ADRP, also known as Perilipin 2 or PLIN2) is a lipid droplet protein regulating the storage and breakdown of fats in cells. SARS-CoV-2 may hijack the lipid handling machinery of host cells and ADRP may play a role in this process. Disrupting ADRP's interaction with the virus may hinder the virus's ability to use lipids for replication and assembly.

p. Neuropilin-1 (NRP1) is a cell surface receptor with roles in blood vessel development, nerve cell guidance, and immune responses. NRP1 may function as a co-receptor for SARS-CoV-2, facilitating viral entry into cells. Blocking NRP1 may disrupt an alternative route of viral entry.

q. EP300 (E1A Binding Protein P300) is a transcriptional coactivator involved in several cellular processes, including growth, differentiation, and apoptosis, through its acetyltransferase activity that modifies histones and non-histone proteins. EP300 facilitates viral entry into cells and upregulates inflammatory cytokine production.

r. Prostaglandin G/H synthase 2 (PTGS2, also known as COX-2) is an enzyme crucial for the production of inflammatory molecules called prostaglandins. PTGS2 plays a role in the inflammatory response that can become severe in COVID-19 and inhibitors (like some NSAIDs) may have benefits in dampening harmful inflammation, but note that prostaglandins have diverse physiological functions.

s. Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) is a chaperone protein that helps other proteins fold correctly and maintains their stability. HSP90AA1 plays roles in cell signaling, survival, and immune responses. HSP90AA1 may interact with numerous viral proteins, but note that it has diverse physiological functions.

t. Matrix metalloproteinase 9 (MMP9), also called gelatinase B, is a zinc-dependent enzyme that breaks down collagen and other components of the extracellular matrix. MMP9 levels increase in severe COVID-19. Overactive MMP9 can damage lung tissue and worsen inflammation. Inhibition of MMP9 may prevent excessive tissue damage and help regulate the inflammatory response.

u. The interleukin-6 (IL-6) pro-inflammatory cytokine (signaling molecule) has a complex role in the immune response and may trigger and perpetuate inflammation. Elevated IL-6 levels are associated with severe COVID-19 cases and cytokine storm. Anti-IL-6 therapies may be beneficial in reducing excessive inflammation in severe COVID-19 cases.

v. The interleukin-10 (IL-10) anti-inflammatory cytokine helps regulate and dampen immune responses, preventing excessive inflammation. IL-10 levels can also be elevated in severe COVID-19. IL-10 could either help control harmful inflammation or potentially contribute to immune suppression.

w. Vascular Endothelial Growth Factor A (VEGFA) promotes the growth of new blood vessels (angiogenesis) and has roles in inflammation and immune responses. VEGFA may contribute to blood vessel leakiness and excessive inflammation associated with severe COVID-19.

x. RELA is a transcription factor subunit of NF-kB and is a key regulator of inflammation, driving pro-inflammatory gene expression. SARS-CoV-2 may hijack and modulate NF-kB pathways.

y. The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.

z. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.

aa. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.

ab. HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.

ac. Huh-7 cells were derived from a liver tumor (hepatoma).

ad. Caco-2 cells come from a colorectal adenocarcinoma (cancer). They are valued for their ability to form a polarized cell layer with properties similar to the intestinal lining.

ae. Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.

af. mTEC is a mouse tubular epithelial cell line.

ag. RAW264.7 is a mouse macrophage cell line.

ah. A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.

ai. A mouse model of obesity and severe insulin resistance leading to type 2 diabetes due to a mutation in the leptin receptor gene that impairs satiety signaling.

aj. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.

Qin et al., 11 Nov 2023, China, peer-reviewed, 8 authors. Contact: epuswei@gmail.com, 874643370@qq.com.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Quercetin All

Exploring the bioactive compounds of Feiduqing formula for the prevention and management of COVID-19 through network pharmacology and molecular docking

Shuang-Lin Qin, Hui Yao, Ting Huang, Hong-Fei Yang, Ting-Ting Ge, Jie-Qiong Wang, Wei-Wu Wang, Qing Min

Medical Data Mining, doi:10.53388/mdm202407003

Background: To explore the effective chemical constituents of Feiduqing formula for prevention and treatment of coronavirus disease 2019 . Methods: The compounds and action targets of twelve herbal medicines in Feiduqing formula were collected via Traditional Chinese Medicine Systems Pharmacology Database and Analytic Platform. The genes corresponding to the targets were queried through the UniProt database. The "herbal medicine-ingredient-target" network was established by Cytoscape software. The Gene Ontology function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed by Database for Annotation, Visualization and Integrated Discovery. Molecular docking was used to analyze the binding force of core active compounds of Feiduqing formula with PTGS2, HSP90AA1, SARS-CoV-2 3CL hydrolase and angiotensin converting enzyme II (ACE2). Results: The "herbal medicine-ingredient-target" network included 434 nodes and 1948 edges, including 222 components such as quercetin, kaempferol, luteolin, etc. The key targets are PTGS2, HSP90AA1, PTGS1, ESR1, AR, NOS2, etc. Gene Ontology function enrichment analysis revealed 2530 items, including RNA polymerase II-specific, response to oxidative stress, transcription factor activity, etc. Kyoto Encyclopedia of Genes and Genomes pathway enrichment screened 169 signal pathways, including Human cytomegalovirus infection, Kaposi sarcoma-associated herpesvirus infection, Hepatitis B, Hepatitis C, IL-17, TNF, etc. The results of molecular docking showed that quercetin, luteolin, β-sitosterol, stigmasterol and other core active compounds have a certain degree of affinity with PTGS2, HSP90AA1, SARS-CoV-2 3CL hydrolase and ACE2. Conclusion: The active compounds of Feiduqing formula may have a therapeutic effect on COVID-19 pneumonia through the action on PTGS2, HSP90AA1, SARS-CoV-2 3CL hydrolase and ACE2, and regulating many signaling pathways.

Competing interests The authors declare no conflicts of interest.

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