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All Studies   Meta Analysis    Recent:   

Discovery of Novel Natural Inhibitors Against SARS-CoV-2 Main Protease: A Rational Approach to Antiviral Therapeutics

Waqas et al., Current Medicinal Chemistry, doi:10.2174/0109298673292839240329081008
Apr 2024  
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Quercetin for COVID-19
22nd treatment shown to reduce risk in July 2021
 
*, now known with p = 0.0031 from 11 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,100+ studies for 60+ treatments. c19early.org
In Silico and In Vitro study showing potential inhibition of SARS-CoV-2 main protease (Mpro) by quercetin and four other natural compounds isolated from medicinal plants. Authors used molecular docking, molecular dynamics simulations, and in vitro enzyme inhibition assays to assess the compounds' binding affinity and inhibitory activity against Mpro. Quercetin showed strong interactions with key residues in the Mpro active site in the computational analysis. In the in vitro assay, quercetin inhibited Mpro with an IC50 of 13.9 μM and exhibited low cytotoxicity (3.5% at 30 μM) in human BJ cell lines.
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spike Note A, Alavi, Azmi (B), Chandran, Kandeil, Mandal, Moschovou, Nguyen, Pan, Thapa (B), Şimşek, Mpro Note B, Akinwumi, Alanzi, Ibeh, Kandeil, Mandal, Moschovou, Nguyen, Qin, Rehman, Sekiou (B), Singh, Thapa (B), Wang, Zhang, Shaik, Waqas, Nalban, Irfan, RNA-dependent RNA polymerase Note C, Corbo, PLpro Note D, Ibeh, Zhang, ACE2 Note E, Chandran, Ibeh, Qin, Thapa (B), Şimşek, Alkafaas, TMPRSS2 Note F, Chandran, helicase Note G, Alanzi, Singh (B), endoribonuclease Note H, Alavi, cathepsin L Note I, Ahmed, Wnt-3 Note J, Chandran, FZD Note K, Chandran, LRP6 Note L, Chandran, ezrin Note M, Chellasamy, ADRP Note N, Nguyen, NRP1 Note O, Şimşek, EP300 Note P, Hasanah, PTGS2 Note Q, Qin, HSP90AA1 Note R, Qin, Hasanah, matrix metalloproteinase 9 Note S, Sai Ramesh, IL-6 Note T, Yang, Yang (B), IL-10 Note U, Yang, VEGFA Note V, Yang (B), and RELA Note W, Yang (B) proteins. In Vitro studies demonstrate efficacy in Calu-3 Note X, DiGuilio, A549 Note Y, Yang, HEK293-ACE2+ Note Z, Singh (C), Huh-7 Note AA, Pan, Caco-2 Note AB, Roy, Vero E6 Note AC, Kandeil, El-Megharbel, Roy, mTEC Note AD, Wu, and RAW264.7 Note AE, Wu cells. Animal studies demonstrate efficacy in K18-hACE2 mice Note AF, Aguado, db/db mice Note AG, Wu, Wu (B), BALB/c mice Note AH, Shaker, and rats El-Megharbel (B). Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice Shaker.
Waqas et al., 5 Apr 2024, peer-reviewed, 10 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
Discovery of Novel Natural Inhibitors Against SARS-CoV-2 Main Protease: A Rational Approach to Antiviral Therapeutics
Muhammad Waqas, Saeed Ullah, Sobia Ahsan Halim, Inam Ullah, Najeeb Ur Rehman, Afnan Jan, Asaad Khalid, Amjad Ali, Ajmal Khan, Ahmed Al-Harrasi
Current Medicinal Chemistry, doi:10.2174/0109298673292839240329081008
Background/Aim: The global pandemic caused by the novel SARS-CoV-2 virus underscores the urgent need for therapeutic interventions. Targeting the virus's main protease (Mpro), crucial for viral replication, is a promising strategy. Objective: The current study aims to discover novel inhibitors of Mpro. Methods: The current study identified five natural compounds (myrrhanol B (C1), myrrhanone B (C2), catechin (C3), quercetin (C4), and feralolide (C5) with strong inhibitory potential against Mpro through virtual screening and computational methods, predicting their binding efficiencies and validated it using the in-vitro inhibition activity. The selected compound's toxicity was examined using the MTT assay on a human BJ cell line. Results: Compound C1 exhibited the highest binding affinity, with a docking score of -9.82 kcal/mol and strong hydrogen bond interactions within Mpro's active site. A microscale molecular dynamics simulation confirmed the stability and tight fit of the compounds in the protein's active pocket, showing superior binding interactions. in vitro assays validated their inhibitory effects, with C1 having the most significant potency (IC50 = 2.85 µM). The non-toxic nature of these compounds in human BJ cell lines was also confirmed, advocating their safety profile. Conclusion: These findings highlight the effectiveness of combining computational and experimental approaches to identify potential lead compounds for SARS-CoV-2, with C1-C5 emerging as promising candidates for further drug development against this virus.
CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.
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{ 'DOI': '10.2174/0109298673292839240329081008', 'ISSN': ['0929-8673'], 'URL': 'http://dx.doi.org/10.2174/0109298673292839240329081008', 'abstract': '<jats:sec>\n' '<jats:title>Background/Aim:</jats:title>\n' '<jats:p>The global pandemic caused by the novel SARS-CoV-2\n' "virus underscores the urgent need for therapeutic interventions. Targeting the virus's\n" 'main protease (Mpro), crucial for viral replication, is a promising strategy.</jats:p>\n' '</jats:sec>\n' '<jats:sec>\n' '<jats:title>Objective:</jats:title>\n' '<jats:p>The current study aims to discover novel inhibitors of Mpro.</jats:p>\n' '</jats:sec>\n' '<jats:sec>\n' '<jats:title>Methods:</jats:title>\n' '<jats:p>The current study identified five natural compounds (myrrhanol B (C1), myrrhanone\n' 'B (C2), catechin (C3), quercetin (C4), and feralolide (C5) with strong inhibitory\n' 'potential against Mpro through virtual screening and computational methods, predicting\n' 'their binding efficiencies and validated it using the in-vitro inhibition activity. The\n' "selected compound's toxicity was examined using the MTT assay on a human BJ cell\n" 'line.</jats:p>\n' '</jats:sec>\n' '<jats:sec>\n' '<jats:title>Results:</jats:title>\n' '<jats:p>Compound C1 exhibited the highest binding affinity, with a docking score of\n' "-9.82 kcal/mol and strong hydrogen bond interactions within Mpro's active site. A microscale\n" 'molecular dynamics simulation confirmed the stability and tight fit of the compounds\n' "in the protein's active pocket, showing superior binding interactions. in vitro assays\n" 'validated their inhibitory effects, with C1 having the most significant potency\n' '(IC50 = 2.85 μM). The non-toxic nature of these compounds in human BJ cell lines was\n' 'also confirmed, advocating their safety profile.</jats:p>\n' '</jats:sec>\n' '<jats:sec>\n' '<jats:title>Conclusion:</jats:title>\n' '<jats:p>These findings highlight the effectiveness of combining computational and\n' 'experimental approaches to identify potential lead compounds for SARS-CoV-2, with\n' 'C1-C5 emerging as promising candidates for further drug development against this\n' 'virus.</jats:p>\n' '</jats:sec>\n' '<jats:sec>\n' '<jats:title>conclusion:</jats:title>\n' '<jats:p>These findings highlight the effectiveness of combining computational and ' 'experimental approaches to identify potential lead compounds for SARS-CoV-2, with C1-C5 ' 'emerging as promising candidates for further drug development against this virus.</jats:p>\n' '</jats:sec>', 'alternative-id': ['LiveAll1'], 'author': [ { 'affiliation': [ { 'name': 'Department of Biotechnology and Genetic Engineering, Hazara ' 'University Mansehra, Mansehra 2100, Pakistan'}], 'family': 'Waqas', 'given': 'Muhammad', 'sequence': 'first'}, { 'affiliation': [ { 'name': 'Natural and Medical Sciences Research Center, University of ' 'Nizwa, Nizwa 616, Sultanate of Oman'}], 'family': 'Ullah', 'given': 'Saeed', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Natural and Medical Sciences Research Center, University of ' 'Nizwa, Nizwa 616, Sultanate of Oman'}], 'family': 'Ahsan Halim', 'given': 'Sobia', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Department of Biotechnology and Genetic Engineering, Hazara ' 'University Mansehra, Mansehra 2100, Pakistan'}], 'family': 'Ullah', 'given': 'Inam', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Natural and Medical Sciences Research Center, University of ' 'Nizwa, Nizwa 616, Sultanate of Oman'}], 'family': 'Najeeb Ur Rehman', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Umm Al-Qura University, Faculty of Medicine, Department of ' 'Biochemistry, Makkah, Kingdom of Saudi Arabia'}], 'family': 'Jan', 'given': 'Afnan', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Substance Abuse and Toxicology Research Center, Jazan ' 'University, P.O. 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