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INTRODUCTION: In our quest to identify potent inhibitors against SARS-CoV-2, an extensive investigation was conducted for the binding and inhibitory efficacy of Rutin against nine SARS-CoV-2 proteins. METHODS: Structure Similarity, flexible alignment, Molecular Docking, molecular dynamics (MD) simulations and in vitro assays against the RdRp and SARS-CoV-2 have been conducted. RESULTS: The first step of our analysis involved a comprehensive examination of structural similarity among the co-crystallized ligands associated with those proteins. A substantial structural similarity was observed between Rutin and Remdesivir, the ligand of the SARS-CoV-2 RNAdependent RNA polymerase (RdRp). This similarity was validated through a flexible alignment study. Molecular docking studies, involving superimposition, revealed a notable resemblance in the mode of binding between Rutin and Remdesivir inside the active site of the RdRp. A 200 ns MD simulation confirmed that the RdRp-Rutin complex is more stable than the RdRp-Remdesivir complex. The MM-GBSA studies showed that Rutin had much more favorable binding energies, with a significantly lower value of -7.76 kcal/mol compared to Remdesivir's -2.15 kcal/mol. This indicates that the RdRp-Rutin binding is more robust and stable. PLIP and ProLIF studies helped clarify the 3D binding interactions and confirmed the stable binding seen in MD simulations. PCAT gave more insights into the dynamic behavior of the RdRp-Rutin complex. In vitro tests showed that Rutin has a strong inhibitory effect on RdRp with an IC50 of 60.09 nM, significantly outperforming Remdesivir, which has an IC50 of 24.56 μM. Remarkably, against SARS-CoV-2, Rutin showed a superior in vitro IC50 of 0.598 μg/ml compared to Remdesivir (12.47 μg/ml). The values of the selectivity index underscored the exceptional margin of safety of Rutin (SI: 1078) compared to Remdesivir (SI: 5.8). CONCLUSION: In conclusion, our comprehensive analysis indicates Rutin's promising potential as a potent SARS-CoV-2 RdRp inhibitor, providing a valuable insight for developing an effective COVID-19 treatment.
Metwaly et al. (Mon,) studied this question.