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Fisetin 8-C-glucoside as entry inhibitor in SARS CoV-2 infection: molecular modelling study.

ABSTRACT: Coronaviruses are RNA viruses that infect varied species including humans. TMPRSS2 is gateway for SARS CoV-2 entry into the host cell. It causes proteolytic activation of spike protein and discharge of the peptide into host cell. The TMPRSS2 inhibition could be one of the approaches to stop the viral entry, therefore, interaction pattern and binding energies for Fisetin and TMPRSS2 have been explored in the present study. TMPRSS2 peptide was used for homology modelling and then for further study. Molecular docking score and MMGBSA Binding energy of Fisetin was better than Nafamostat, a known inhibitor of TMPRSS2. Post docking MM-GBSA free energy for Fisetin and Nafamostat was -42.78 and -21.11 kcal/mol, respectively. Fisetin forms H bond with Val 25, His 41, Lys 42, Lys 45, Glu 44, Ser186. Nafamostat formed H bonds with Lys 85, Asp 90, Asp 203. RMSD plots of TMPRSS2, TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex showed stable profile with very small fluctuation during entire simulation of 150 ns. Significant decrease in TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex fluctuation occurred around His 41, Glu 44, Gly 136, Ser 186 in RMSF study. During simulation Fisetin interaction was observed with residues Val 25, His 41, Glu 44, Lys 45, Lys 87, Gly 136, Gln 183, Ser 186 likewise interaction of Nafamostat with Lys 85, Asp 90, Asn 163, Asp 203 and Ser 205. Post simulation MM-GBSA free energy was found to be -51.87 ± 4.3 and -48.23 ± 4.39 kcal/mol for TMPRSS2 with Fisetin and Nafamostat, respectively. Communicated by Ramaswamy H. Sarma.

SUBMITTER: Mishra A

PROVIDER: S-EPMC7784833 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The COVID-19 pandemic has disrupted delivery of immunisation services globally. Many countries have postponed vaccination campaigns out of concern about infection risks to staff delivering vaccination, the children being vaccinated and their families. The World Health Organization recommends considering both the benefit of preventive campaigns and the risk of SARS-CoV-2 transmission when making decisions about campaigns during COVID-19 outbreaks, but there has been little quantification of the risks. We modelled excess SARS-CoV-2 infection risk to vaccinators, vaccinees and their caregivers resulting from vaccination campaigns delivered during a COVID-19 epidemic. Our model used population age-structure and contact patterns from three exemplar countries (Burkina Faso, Ethiopia, and Brazil). It combined an existing compartmental transmission model of an underlying COVID-19 epidemic with a Reed-Frost model of SARS-CoV-2 infection risk to vaccinators and vaccinees. We explored how excess risk depends on key parameters governing SARS-CoV-2 transmissibility, and aspects of campaign delivery such as campaign duration, number of vaccinations, and effectiveness of personal protective equipment (PPE) and symptomatic screening. Infection risks differ considerably depending on the circumstances in which vaccination campaigns are conducted. A campaign conducted at the peak of a SARS-CoV-2 epidemic with high prevalence and without special infection mitigation measures could increase absolute infection risk by 32% to 45% for vaccinators, and 0.3% to 0.5% for vaccinees and caregivers. However, these risks could be reduced to 3.6% to 5.3% and 0.1% to 0.2% respectively by use of PPE that reduces transmission by 90% (as might be achieved with N95 respirators or high-quality surgical masks) and symptomatic screening. SARS-CoV-2 infection risks to vaccinators, vaccinees and caregivers during vaccination campaigns can be greatly reduced by adequate PPE, symptomatic screening, and appropriate campaign timing. Our results support the use of adequate risk mitigation measures for vaccination campaigns held during SARS-CoV-2 epidemics, rather than cancelling them entirely.

Project description:BackgroundThe COVID-19 pandemic has disrupted the delivery of immunisation services globally. Many countries have postponed vaccination campaigns out of concern about infection risks to the staff delivering vaccination, the children being vaccinated, and their families. The World Health Organization recommends considering both the benefit of preventive campaigns and the risk of SARS-CoV-2 transmission when making decisions about campaigns during COVID-19 outbreaks, but there has been little quantification of the risks.MethodsWe modelled excess SARS-CoV-2 infection risk to vaccinators, vaccinees, and their caregivers resulting from vaccination campaigns delivered during a COVID-19 epidemic. Our model used population age structure and contact patterns from three exemplar countries (Burkina Faso, Ethiopia, and Brazil). It combined an existing compartmental transmission model of an underlying COVID-19 epidemic with a Reed-Frost model of SARS-CoV-2 infection risk to vaccinators and vaccinees. We explored how excess risk depends on key parameters governing SARS-CoV-2 transmissibility, and aspects of campaign delivery such as campaign duration, number of vaccinations, and effectiveness of personal protective equipment (PPE) and symptomatic screening.ResultsInfection risks differ considerably depending on the circumstances in which vaccination campaigns are conducted. A campaign conducted at the peak of a SARS-CoV-2 epidemic with high prevalence and without special infection mitigation measures could increase absolute infection risk by 32 to 45% for vaccinators and 0.3 to 0.5% for vaccinees and caregivers. However, these risks could be reduced to 3.6 to 5.3% and 0.1 to 0.2% respectively by use of PPE that reduces transmission by 90% (as might be achieved with N95 respirators or high-quality surgical masks) and symptomatic screening.ConclusionsSARS-CoV-2 infection risks to vaccinators, vaccinees, and caregivers during vaccination campaigns can be greatly reduced by adequate PPE, symptomatic screening, and appropriate campaign timing. Our results support the use of adequate risk mitigation measures for vaccination campaigns held during SARS-CoV-2 epidemics, rather than cancelling them entirely.

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Fisetin 8-C-glucoside as entry inhibitor in SARS CoV-2 infection: molecular modelling study.

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