Thesis (Ph.D)-Cairo University,2022.

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Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) considers the major global health disaster in 2019-20. Globally, until now, there have highest percentage of viral inhibition and were the most promising drugs against SARS-CoV-2. This study encourages us to continue studying to conduct more clinical trials to test the viral inhibition of these drugs on cancer patients who receives these drugs. been approximately 600 million confirmed cases of COVID-19, with more than 6 million deaths and approximately 570 million recovered. Egypt has approximately 515,000 confirmed cases with 24613 deaths. Till now, there are no targeted therapies for COVID-19. Hence, the drug repurposing strategy of the existing drug may provide a successful outcome for COVID-19 patients with low cost and fast return. Aim of the work: This thesis aims to reveal the variants of SARS CoV-2 and their mutations found in Egypt and to study the action of some available drug compounds on SARS-CoV-2 proteins’ active site through in silico study and to investigate the antiviral effect of these drug compounds using in vitro study. Methods: SARS COV-2 positive samples with high titer were sequenced using Next Generation sequencing to identify the viral variants in Egypt. Then, Homology modeling of viral proteins was performed using modeller software. After that, Docking of our studied drugs versus viral proteins was achieved using Schrodinger software. Cytotoxicity of all materials was studied on VERO E6 cells using an MTT assay. Finally, the antiviral activities of the studied drugs were assessed using plaque assay. Results: Sequencing analysis showed that genomic strains found in Egypt are similar to isolates from England, Brazil, and South Africa. Molecular Docking analysis of the in-silico study revealed binding affinity scores with Mpro, N, Mpro, N, and M of -6.9±0.7Kcal/mol, -7.0Kcal/mol, -7.2±1.0Kcal/mol, -6.7Kcal/mol and - 5.6Kcal/mol for Clofazimine, Tolvaptan, Idelalisib, Olaparib, Ponatinib respectively. In vitro study showed that both Tolvaptan and Clofazimine had the highest percentage of viral inhibition by 73% and 61%, respectively. Conclusion: Most Egyptian genomic strains sequenced are similar to isolates from England, Brazil, and South Africa. This data demonstrated the relative increase of the B.1.1.1 lineages over the B.1. In Egyptian samples, a new clade 20B was discovered using the next strain nomenclature. All studied compounds displayed antiviral activity against SARS-CoV-2 in VERO E6 cell lines. Both Tolvaptan and Clofazimin had the