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In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural inhibitors of SARS-CoV-2 Mpro

Naderi Beni et al., PLOS ONE, doi:10.1371/journal.pone.0295014

Nov 2023

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Curcumin for COVID-19

15th treatment shown to reduce risk in February 2021, now with p = 0.0000000096 from 27 studies.

Lower risk for mortality, ventilation, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

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

In Silico study showing potential benefits of the phytochemicals curcumin, savinin, and betulinic acid as an inhibitor of the SARS-CoV-2 main protease (M^pro). Molecular docking analysis revealed these hot temperament, antioxidant compounds bind strongly to both monomeric and dimeric forms of M^pro, with the higest predicted binding affinity for betulinic acid. MD simulations confirmed curcumin forms multiple hydrogen bonds with active site residues. MM-PBSA calculations also showed favorable binding free energy for the curcumin-M^pro complex. Additionally, ADMET analysis revealed curcumin satisfies criteria for drug-likeness. By targeting the viral protease, curcumin may inhibit SARS-CoV-2 replication.

48 preclinical studies support the efficacy of curcumin for COVID-19:

24 In Silico studies1-24

23 In Vitro studies1,5,7,11,17,21,25-41

1 In Vivo animal study5

In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,5,10,12,18,21 (and specifically the receptor binding domainB,8,11,14), M^proC,5,7,9-11,13,14,16,19,21,22,24,38, RNA-dependent RNA polymeraseD,11,20, ACE2E,12,13,15, nucleocapsidF,6,23, nsp10G,23, and helicaseH,27 proteins. In Vitro studies demonstrate inhibition of the spikeA,32 (and specifically the receptor binding domainB,41), M^proC,17,32,38,40, ACE2E,41, and TMPRSS2I,41 proteins, and inhibition of spike-ACE2 interactionJ,25. In Vitro studies demonstrate efficacy in Calu-3K,39, A549L,32, 293TM,1, HEK293-hACE2N,17,30, 293T/hACE2/TMPRSS2O,31, Vero E6P,7,11,21,30,32,34,35,37,39, and SH-SY5YQ,29 cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants8, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells37, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress1, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts42, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity33.

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14. Srivastava et al., Paradigm of Well-Orchestrated Pharmacokinetic Properties of Curcuminoids Relative to Conventional Drugs for the Inactivation of SARS-CoV-2 Receptors: An In Silico Approach, Stresses, doi:10.3390/stresses3030043.mdpi.com, doi.org.

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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 receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.

c. 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.

d. 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.

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. 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.

g. Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.

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. 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.

j. 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.

k. 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.

l. 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.

m. 293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.

n. HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.

o. 293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.

p. 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.

q. SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.

Naderi Beni et al., 30 Nov 2023, peer-reviewed, 4 authors. Contact: a.seyedarabi@ut.ac.ir, s.gharaghani@ut.ac.ir.

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

This Paper Curcumin All

In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural inhibitors of SARS-CoV-2 Mpro

Ramin Naderi Beni, Parisa Elyasi-Ebli, Sajjad Gharaghani, Arefeh Seyedarabi

PLOS ONE, doi:10.1371/journal.pone.0295014

Main protease (M pro ) of SARS-CoV-2 is considered one of the key targets due to its role in viral replication. The use of traditional phytochemicals is an important part of complementary/alternative medicine, which also accompany the concept of temperament, where it has been shown that hot medicines cure cold and cold medicines cure hot, with cold and hot pattern being associated with oxidative and anti-oxidative properties in medicine, respectively. Molecular docking in this study has demonstrated that a number of anti-oxidative and hot temperament-based phytochemicals have high binding affinities to SARS-CoV-2 M pro , both in the monomeric and dimeric deposited states of the protein. The highest ranking phytochemicals identified in this study included savinin, betulinic acid and curcumin. Complexes of savinin, betulinic acid, curcumin as well as Nirmatrelvir (the only approved inhibitor, used for comparison) bound to SARS-CoV-2 M pro were further subjected to molecular dynamics simulations. Subsequently, RMSD, RMSF, Rg, number of hydrogen bonds, binding free energies and residue contributions (using MM-PBSA) and buried surface area (BSA), were analysed. The computational results suggested high binding affinities of savinin, betulinic acid and curcumin to both the monomeric and dimeric deposited states of M pro , while highlighting the lower binding energy of betulinic acid in comparison with savinin and curcumin and even Nirmatrelvir, leading to a greater stability of the betulinic acid-SARS-CoV-2 M pro complex. Overall, based on the increasing mutation rate in the spike protein and the fact that the SARS-CoV-2 M pro remains highly conserved, this study provides an insight into the use of phytochemicals against COVID-19 and other coronavirus diseases.

Richards and Lee method with a water probe size of 1.4 Å [63] . Subsequently, the BSA was calculated using the formula BSA = 0.5*(SASA ligand + SASA protein-SASA complex). Supporting information S1

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{ 'indexed': {'date-parts': [[2023, 12, 1]], 'date-time': '2023-12-01T00:32:49Z', 'timestamp': 1701390769979}, 'reference-count': 63, 'publisher': 'Public Library of Science (PLoS)', 'issue': '11', 'license': [ { 'start': { 'date-parts': [[2023, 11, 30]], 'date-time': '2023-11-30T00:00:00Z', 'timestamp': 1701302400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': ['www.plosone.org'], 'crossmark-restriction': False}, 'abstract': 'Main protease (Mpro) of SARS-CoV-2 is considered one of the key ' 'targets due to its role in viral replication. The use of traditional phytochemicals is an ' 'important part of complementary/alternative medicine, which also accompany the concept of ' 'temperament, where it has been shown that hot medicines cure cold and cold medicines cure ' 'hot, with cold and hot pattern being associated with oxidative and anti-oxidative properties ' 'in medicine, respectively. Molecular docking in this study has demonstrated that a number of ' 'anti-oxidative and hot temperament-based phytochemicals have high binding affinities to ' 'SARS-CoV-2 Mpro, both in the monomeric and dimeric deposited states of ' 'the protein. The highest ranking phytochemicals identified in this study included savinin, ' 'betulinic acid and curcumin. Complexes of savinin, betulinic acid, curcumin as well as ' 'Nirmatrelvir (the only approved inhibitor, used for comparison) bound to SARS-CoV-2 ' 'Mpro were further subjected to molecular dynamics simulations. ' 'Subsequently, RMSD, RMSF, Rg, number of hydrogen bonds, binding free energies and residue ' 'contributions (using MM-PBSA) and buried surface area (BSA), were analysed. The computational ' 'results suggested high binding affinities of savinin, betulinic acid and curcumin to both the ' 'monomeric and dimeric deposited states of Mpro, while highlighting the ' 'lower binding energy of betulinic acid in comparison with savinin and curcumin and even ' 'Nirmatrelvir, leading to a greater stability of the betulinic acid-SARS-CoV-2 ' 'Mpro complex. Overall, based on the increasing mutation rate in the ' 'spike protein and the fact that the SARS-CoV-2 Mpro remains highly ' 'conserved, this study provides an insight into the use of phytochemicals against COVID-19 and ' 'other coronavirus diseases.', 'DOI': '10.1371/journal.pone.0295014', 'type': 'journal-article', 'created': { 'date-parts': [[2023, 11, 30]], 'date-time': '2023-11-30T18:54:48Z', 'timestamp': 1701370488000}, 'page': 'e0295014', 'update-policy': 'http://dx.doi.org/10.1371/journal.pone.corrections_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural ' 'inhibitors of SARS-CoV-2 Mpro', 'prefix': '10.1371', 'volume': '18', 'author': [ {'given': 'Ramin', 'family': 'Naderi Beni', 'sequence': 'first', 'affiliation': []}, {'given': 'Parisa', 'family': 'Elyasi-Ebli', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sajjad', 'family': 'Gharaghani', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-4234-9799', 'authenticated-orcid': True, 'given': 'Arefeh', 'family': 'Seyedarabi', 'sequence': 'additional', 'affiliation': []}], 'member': '340', 'published-online': {'date-parts': [[2023, 11, 30]]}, 'reference': [ { 'key': 'pone.0295014.ref001', 'volume-title': 'StatPearls', 'author': 'M Cascella', 'year': '2021'}, { 'issue': '3', 'key': 'pone.0295014.ref002', 'article-title': 'Coronavirus disease: a review of a new threat to public health', 'volume': '12', 'author': 'K. 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Lee', 'year': '1971', 'journal-title': 'J Mol Biol.'}], 'container-title': 'PLOS ONE', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://dx.plos.org/10.1371/journal.pone.0295014', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 11, 30]], 'date-time': '2023-11-30T18:55:24Z', 'timestamp': 1701370524000}, 'score': 1, 'resource': {'primary': {'URL': 'https://dx.plos.org/10.1371/journal.pone.0295014'}}, 'subtitle': [], 'editor': [{'given': 'Ahmed A.', 'family': 'Al-Karmalawy', 'sequence': 'first', 'affiliation': []}], 'short-title': [], 'issued': {'date-parts': [[2023, 11, 30]]}, 'references-count': 63, 'journal-issue': {'issue': '11', 'published-online': {'date-parts': [[2023, 11, 30]]}}, 'URL': 'http://dx.doi.org/10.1371/journal.pone.0295014', 'relation': {}, 'ISSN': ['1932-6203'], 'subject': ['Multidisciplinary'], 'container-title-short': 'PLoS ONE', 'published': {'date-parts': [[2023, 11, 30]]}}

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