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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
24th treatment shown to reduce risk in July 2021, now with p = 0.0031 from 11 studies.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 109 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.
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
71 preclinical studies support the efficacy of quercetin for COVID-19:
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,2,8,9,21,23,24,29,37,38,40,41,61-63, MproB,2,6,8,10,12,14,16,17,19,22,23,29,33,35-37,41,42,44,62-64, RNA-dependent RNA polymeraseC,2,8,31,63, PLproD,2,36,44, ACE2E,21,22,27,36,40,62, TMPRSS2F,21, nucleocapsidG,2, helicaseH,2,28,33, endoribonucleaseI,38, NSP16/10J,5, cathepsin LK,25, Wnt-3L,21, FZDM,21, LRP6N,21, ezrinO,39, ADRPP,37, NRP1Q,40, EP300R,15, PTGS2S,22, HSP90AA1T,15,22, matrix metalloproteinase 9U,30, IL-6V,20,34, IL-10W,20, VEGFAX,34, and RELAY,34 proteins. In Vitro studies demonstrate inhibition of the MproB,14,45,50,58 protein, and inhibition of spike-ACE2 interactionZ,46. In Vitro studies demonstrate efficacy in Calu-3AA,49, A549AB,20, HEK293-ACE2+AC,57, Huh-7AD,24, Caco-2AE,48, Vero E6AF,18,41,48, mTECAG,51, and RAW264.7AH,51 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAI,54, db/db miceAJ,51,60, BALB/c miceAK,59, and rats65. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice59, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages4, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity53.
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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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. 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