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Phytoconstituents of Citrus limon (Lemon) as Potential Inhibitors Against Multi Targets of SARS‐CoV‐2 by Use of Molecular Modelling and In Vitro Determination Approaches

Raman et al., ChemistryOpen, doi:10.1002/open.202300198
Jun 2024  
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Quercetin for COVID-19
24th treatment shown to reduce risk in July 2021, now with p = 0.002 from 12 studies.
Lower risk for ICU, hospitalization, recovery, cases, and viral clearance.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 112 treatments. c19early.org
In Silico study showing potential benefits of quercetin for COVID-19. Authors found that quercetin exhibited significant binding affinity to three SARS-CoV-2 targets: main protease (Mpro), spike glycoprotein, and RNA-dependent RNA polymerase (RdRp). The computational analysis revealed quercetin had a Glide score of -7.41 kcal/mol for Mpro, -5.36 kcal/mol for spike protein, and -7.02 kcal/mol for RdRp, indicating strong binding potential. These scores were more favorable than those of standard COVID-19 drugs like remdesivir. Molecular dynamics simulations over 100ns further supported the stability of quercetin's interactions with these viral proteins. ADMET screening suggested favorable pharmacokinetic characteristics. Authors did not include quercetin in their in vitro analysis, which focused on other compounds.
73 preclinical studies support the efficacy of quercetin for COVID-19:
45 In Silico studies1-45
22 In Vitro studies1,2,5,15,19,21,25,42,46-59
6 In Vivo animal studies5,19,52,55,60,61
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,3,9,10,22,24,25,30,38,39,41,42,62-64, MproB,3,7,9,11,13,15,17,18,20,23,24,30,34,36-38,42,43,45,63-65, RNA-dependent RNA polymeraseC,1,3,9,32,64, PLproD,3,37,45, ACE2E,22,23,28,37,41,63, TMPRSS2F,22, nucleocapsidG,3, helicaseH,3,29,34, endoribonucleaseI,39, NSP16/10J,6, cathepsin LK,26, Wnt-3L,22, FZDM,22, LRP6N,22, ezrinO,40, ADRPP,38, NRP1Q,41, EP300R,16, PTGS2S,23, HSP90AA1T,16,23, matrix metalloproteinase 9U,31, IL-6V,21,35, IL-10W,21, VEGFAX,35, and RELAY,35 proteins. In Vitro studies demonstrate inhibition of the MproB,15,46,51,59 protein, and inhibition of spike-ACE2 interactionZ,47. In Vitro studies demonstrate efficacy in Calu-3AA,50, A549AB,21, HEK293-ACE2+AC,58, Huh-7AD,25, Caco-2AE,49, Vero E6AF,19,42,49, mTECAG,52, and RAW264.7AH,52 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAI,55, db/db miceAJ,52,61, BALB/c miceAK,60, and rats66. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice60, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages5, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity54.
Important missing comments or errors? Let us know.
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 Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro 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 nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
h. 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.
i. 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.
j. 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.
k. 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. Wingless-related integration site (Wnt) ligand 3 is a host signaling molecule that activates the Wnt signaling pathway, which is important in development, cell growth, and tissue repair. Some studies suggest that SARS-CoV-2 infection may interfere with the Wnt signaling pathway, and that Wnt3a is involved in SARS-CoV-2 entry.
m. 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.
n. 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.
o. 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.
p. 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.
q. 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.
r. 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.
s. 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.
t. 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.
u. 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.
v. 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.
w. 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.
x. 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.
y. 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.
z. 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.
aa. 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.
ab. 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.
ac. HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.
ad. Huh-7 cells were derived from a liver tumor (hepatoma).
ae. 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.
af. 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.
ag. mTEC is a mouse tubular epithelial cell line.
ah. RAW264.7 is a mouse macrophage cell line.
ai. A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
aj. 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.
ak. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
Raman et al., 21 Jun 2024, peer-reviewed, 16 authors. Contact: rkalirajan@jssuni.edu.in, bourhiamohammed@gmail.com.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
Phytoconstituents of Citrus limon (Lemon) as Potential Inhibitors Against Multi Targets of SARS‐CoV‐2 by Use of Molecular Modelling and In Vitro Determination Approaches
Kannan Raman, Rajagopal Kalirajan, Fahadul Islam, Srikanth Jupudi, Divakar Selvaraj, Gomathi Swaminathan, Laliteshwar Pratap Singh, Ritesh Rana, Shopnil Akash, Md. Rezaul Islam, Firzan Nainu, Talha Bin Emran, Turki M Dawoud, Mohammed Bourhia, Musaab Dauelbait, Rashu Barua
ChemistryOpen, doi:10.1002/open.202300198
Musaab Dauelbait, [i
Author Contributions Conceptualization, writing the original draft, formal analysis: Kannan Raman, Rajagopa Kalirajan, Fahadul Islam, Srikanth Jupudi, Divakar Selvaraj, Gomathi Swaminathan, Laliteshwar Pratap Singh. Investigations, funding acquisition, resources, project administration, reviewing and editing: Shopnil Akash, Md. Rezaul Islam, Ritesh Rana, Firzan Nainu. Data validation, and reviewing and editing: Talha Bin Emran, Turki M. Dawoud, Mohammed bourhia, and Rashu Barua. Conflict of Interests The authors declare no conflict of interest. RESEARCH ARTICLE This research has conducted a combine experiment both in vitro, and computational analysis to investigate the potential efficacy of phytoconstituents present in Citrus limon (lemon) against SARS-CoV-2. Overall analysis has reported that a significant binding affinity against the targeted proteins which is shown by phytoconstituents such as Rutin, Eryocitrin, Naringin, and Hesperidine, indicating that these compounds may be useful treatments option against COVID-19 and immunomodulators. However, further clinical research is need in broad scale to confirm these finding.
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Docking was done by glide model, QikProp was performed by <jats:italic>in ' 'silico</jats:italic> ADMET screening &amp; Prime MM‐GB/SA modules were used to define binding ' 'energy. When compared with approved COVID‐19 drugs such as Remdesivir, Ritonavir, Lopinavir, ' 'and Hydroxychloroquine, plant‐based constituents such as Quercetin, Rutoside, Naringin, ' 'Eriocitrin, and Hesperidin. bind with significant G‐scores to the active SARS‐CoV‐2 place. ' 'The constituents Rutoside and Eriocitrin were studied in each MD simulation in 100\u2005ns ' 'against 3 proteins 5R82.<jats:italic>pdb</jats:italic>, 6YZ5.<jats:italic>pdb</jats:italic> ' 'and 7BTF.<jats:italic>pdb</jats:italic>.We performed an assay with significant natural ' 'compounds from contacts and <jats:italic>in silico</jats:italic> results (Rutin, Eriocitrin, ' 'Naringin, Hesperidin) using 3CL protease assay kit (B.11529 Omicron variant). This kit ' 'contained 3CL inhibitor GC376 as Control. The IC<jats:sub>50</jats:sub> value of the test ' 'compound was found to be Rutin −17.50\u2005μM, Eriocitrin−37.91\u2005μM, Naringin−39.58\u2005' 'μM, Hesperidine−140.20\u2005μM, the standard inhibitory concentration of GC376 was 38.64\u2005' 'μM. The phytoconstituents showed important interactions with SARS‐CoV‐2 targets, and ' 'potential modifications could be beneficial for future development.</jats:p>', 'DOI': '10.1002/open.202300198', 'type': 'journal-article', 'created': {'date-parts': [[2024, 6, 21]], 'date-time': '2024-06-21T12:19:53Z', 'timestamp': 1718972393000}, 'update-policy': 'http://dx.doi.org/10.1002/crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Phytoconstituents of <i>Citrus limon</i> (Lemon) as Potential Inhibitors Against Multi Targets ' 'of SARS‐CoV‐2 by Use of Molecular Modelling and <i>In\u2005Vitro</i> Determination Approaches', 'prefix': '10.1002', 'author': [ { 'given': 'Kannan', 'family': 'Raman', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Pharmaceutical Chemistry JSS College of Pharmacy ' 'JSS Academy of Higher Education &amp; Research Ooty 643001 The ' 'Nilgiris, Tamilnadu India'}]}, { 'given': 'Rajagopal', 'family': 'Kalirajan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmaceutical Chemistry JSS College of Pharmacy ' 'JSS Academy of Higher Education &amp; Research Ooty 643001 The ' 'Nilgiris, Tamilnadu India'}]}, { 'given': 'Fahadul', 'family': 'Islam', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmacy Faculty of Allied Health Sciences ' 'Daffodil International University Dhaka 1207 Bangladesh'}]}, { 'given': 'Srikanth', 'family': 'Jupudi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmaceutical Chemistry JSS College of Pharmacy ' 'JSS Academy of Higher Education &amp; Research Ooty 643001 The ' 'Nilgiris, Tamilnadu India'}]}, { 'given': 'Divakar', 'family': 'Selvaraj', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmaceutical Chemistry JSS College of Pharmacy ' 'JSS Academy of Higher Education &amp; Research Ooty 643001 The ' 'Nilgiris, Tamilnadu India'}]}, { 'given': 'Gomathi', 'family': 'Swaminathan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmaceutical Chemistry JSS College of Pharmacy ' 'JSS Academy of Higher Education &amp; Research Ooty 643001 The ' 'Nilgiris, Tamilnadu India'}]}, { 'given': 'Laliteshwar Pratap', 'family': 'Singh', 'sequence': 'additional', 'affiliation': [ { 'name': 'Narayan Institute of Pharmacy Gopal Narayan Singh University ' 'Jamuhar Sasaram (Rohtas) 821305 Bihar India'}]}, { 'given': 'Ritesh', 'family': 'Rana', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmaceutical Sciences (Pharmaceutics) Himachal ' 'Institute of Pharmaceutical Education and Research (HIPER) ' 'Bela, Nadaun Hamirpur, Himachal Pradesh 177042 India'}]}, { 'given': 'Shopnil', 'family': 'Akash', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmacy Faculty of Allied Health Sciences ' 'Daffodil International University Dhaka 1207 Bangladesh'}]}, { 'given': 'Md. Rezaul', 'family': 'Islam', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmacy Faculty of Allied Health Sciences ' 'Daffodil International University Dhaka 1207 Bangladesh'}]}, { 'given': 'Firzan', 'family': 'Nainu', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmacy Faculty of Pharmacy Hasanuddin ' 'University Makassar 90245 Indonesia'}]}, { 'given': 'Talha Bin', 'family': 'Emran', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pharmacy Faculty of Allied Health Sciences ' 'Daffodil International University Dhaka 1207 Bangladesh'}, { 'name': 'Department of Pharmacy BGC Trust University Bangladesh ' 'Chittagong 4381 Bangladesh'}]}, { 'given': 'Turki M.', 'family': 'Dawoud', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Botany and Microbiology College of Science King ' 'Saud University P. O. 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