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1.
Biophys Chem ; 288: 106854, 2022 09.
Article in English | MEDLINE | ID: covidwho-1906814

ABSTRACT

Molecular docking of 234 unique compounds identified in the softwood bark (W set) is presented with a focus on their inhibition potential to the main protease of the SARS-CoV-2 virus 3CLpro (6WQF). The docking results are compared with the docking results of 866 COVID19-related compounds (S set). Furthermore, machine learning (ML) prediction of docking scores of the W set is presented using the S set trained TensorFlow, XGBoost, and SchNetPack ML approaches. Docking scores are evaluated with the Autodock 4.2.6 software. Four compounds in the W set achieve a docking score below -13 kcal/mol, with (+)-lariciresinol 9'-p-coumarate (CID 11497085) achieving the best docking score (-15 kcal/mol) within the W and S sets. In addition, 50% of W set docking scores are found below -8 kcal/mol and 25% below -10 kcal/mol. Therefore, the compounds identified in the softwood bark, show potential for antiviral activity upon extraction or further derivatization. The W set molecular docking studies are validated by means of molecular dynamics (five best compounds). The solubility (Log S, ESOL) and druglikeness of the best docking compounds in S and W sets are compared to evaluate the pharmacological potential of compounds identified in softwood bark.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/pharmacology , Machine Learning , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases , Plant Bark , Protease Inhibitors/pharmacology
2.
Virology ; 569: 13-28, 2022 04.
Article in English | MEDLINE | ID: covidwho-1740261

ABSTRACT

Emerging mutations in the SARS-CoV-2 genome pose a challenge for vaccine development and antiviral therapy. The antiviral efficacy of Azadirachta indica bark extract (NBE) was assessed against SARS-CoV-2 and m-CoV-RSA59 infection. Effects of in vivo intranasal or oral NBE administration on viral load, inflammatory response, and histopathological changes were assessed in m-CoV-RSA59-infection. NBE administered inhibits SARS-CoV-2 and m-CoV-RSA59 infection and replication in vitro, reducing Envelope and Nucleocapsid gene expression. NBE ameliorates neuroinflammation and hepatitis in vivo by restricting viral replication and spread. Isolated fractions of NBE enriched in Nimbin isomers shows potent inhibition of m-CoV-RSA59 infection in vitro. In silico studies revealed that NBE could target Spike and RdRp of m-CoV and SARS-CoV-2 with high affinity. NBE has a triterpenoids origin that may allow them to competitively target panoply of viral proteins to inhibit mouse and different strains of human coronavirus infections, suggesting its potential as an antiviral against pan-ß-Coronaviruses.


Subject(s)
Azadirachta , COVID-19 , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , Limonins , Mice , Plant Bark , Plant Extracts/pharmacology , SARS-CoV-2 , Virus Replication
3.
Molecules ; 25(8)2020 Apr 18.
Article in English | MEDLINE | ID: covidwho-1450861

ABSTRACT

(1) Background: Viral respiratory infections cause life-threatening diseases in millions of people worldwide every year. Human coronavirus and several picornaviruses are responsible for worldwide epidemic outbreaks, thus representing a heavy burden to their hosts. In the absence of specific treatments for human viral infections, natural products offer an alternative in terms of innovative drug therapies. (2) Methods: We analyzed the antiviral properties of the leaves and stem bark of the mulberry tree (Morus spp.). We compared the antiviral activity of Morus spp. on enveloped and nonenveloped viral pathogens, such as human coronavirus (HCoV 229E) and different members of the Picornaviridae family-human poliovirus 1, human parechovirus 1 and 3, and human echovirus 11. The antiviral activity of 12 water and water-alcohol plant extracts of the leaves and stem bark of three different species of mulberry-Morus alba var. alba, Morus alba var. rosa, and Morus rubra-were evaluated. We also evaluated the antiviral activities of kuwanon G against HCoV-229E. (3) Results: Our results showed that several extracts reduced the viral titer and cytopathogenic effects (CPE). Leaves' water-alcohol extracts exhibited maximum antiviral activity on human coronavirus, while stem bark and leaves' water and water-alcohol extracts were the most effective on picornaviruses. (4) Conclusions: The analysis of the antiviral activities of Morus spp. offer promising applications in antiviral strategies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Morus/chemistry , Plant Extracts/pharmacology , Respiratory Tract Infections/drug therapy , Antiviral Agents/therapeutic use , Cell Line , Cytopathogenic Effect, Viral/drug effects , Flavonoids/pharmacology , Humans , Mass Spectrometry , Microbial Sensitivity Tests , Picornaviridae/drug effects , Plant Bark/chemistry , Plant Extracts/therapeutic use , Plant Leaves/chemistry
4.
Int J Mol Sci ; 22(13)2021 Jun 23.
Article in English | MEDLINE | ID: covidwho-1282518

ABSTRACT

The usefulness of anti-inflammatory drugs as an adjunct therapy to improve outcomes in COVID-19 patients is intensely discussed in this paper. Willow bark (Salix cortex) has been used for centuries to relieve pain, inflammation, and fever. Its main active ingredient, salicin, is metabolized in the human body into salicylic acid, the precursor of the commonly used pain drug acetylsalicylic acid (ASA). Here, we report on the in vitro anti-inflammatory efficacy of two methanolic Salix extracts, standardized to phenolic compounds, in comparison to ASA in the context of a SARS-CoV-2 peptide challenge. Using SARS-CoV-2 peptide/IL-1ß- or LPS-activated human PBMCs and an inflammatory intestinal Caco-2/HT29-MTX co-culture, Salix extracts, and ASA concentration-dependently suppressed prostaglandin E2 (PGE2), a principal mediator of inflammation. The inhibition of COX-2 enzyme activity, but not protein expression was observed for ASA and one Salix extract. In activated PBMCs, the suppression of relevant cytokines (i.e., IL-6, IL-1ß, and IL-10) was seen for both Salix extracts. The anti-inflammatory capacity of Salix extracts was still retained after transepithelial passage and liver cell metabolism in an advanced co-culture model system consisting of intestinal Caco-2/HT29-MTX cells and differentiated hepatocyte-like HepaRG cells. Taken together, our in vitro data suggest that Salix extracts might present an additional anti-inflammatory treatment option in the context of SARS-CoV-2 peptides challenge; however, more confirmatory data are needed.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Aspirin/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Plant Extracts/pharmacology , Anti-Inflammatory Agents/chemistry , Benzyl Alcohols/metabolism , COVID-19/virology , Caco-2 Cells , Cyclooxygenase 2/drug effects , Cytokines/metabolism , Dinoprostone/metabolism , Glucosides/metabolism , HT29 Cells , Humans , Inflammation , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/immunology , Plant Bark/chemistry , Plant Extracts/chemistry , SARS-CoV-2/immunology
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