Assessing Dietary Polyphenols' Inhibitory Potential Against SARS-CoV-2RNA-Dependent RNA Polymerase: Structural Insights and Implicationsfor Indian Variants

Introduction: COVID-19, arising from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged as a worldwide pandemic and posed a significant risk to the global healthcare system since early 2020. Accelerated dissemination of SARS-CoV-2 and frequent mutations in its genome have raised concerns about the efficacy of existing therapeutic approaches. As a key enzyme in SARS-CoV-2 replication, RNA-dependent RNA polymerase (RdRp) is a viable target for the development of antiviral drugs. The potential of dietary polyphenols as RdRp inhibitors has not been fully explored, especially in the context of variant-specific mutations, despite substantial research on antiviral medications like remdesivir. This study advances the field of RdRp inhibitor research by focusing on plant-based polyphenols and evaluating their binding stability against mutated RdRp in Indian SARS-CoV-2 variants, offering novel strategies to counter mutation-driven resistance. Methods: In this study, we examined the binding interactions between polyphenols and SARSCoV-2 RdRp using bioinformatic approaches to assess their therapeutic potential against COVID19. Additionally, the structural dynamics of the mutated RdRp protein were analyzed, and molecular docking was conducted with the top compounds to determine whether the mutation influenced their binding affinity. Results: Four polyphenols, namely 10'-hydroxyusambarensine, Cyanidin 3-arabinoside, Cordifolide A, and Usararotenoid A, exhibited higher binding affinity to SARS-CoV-2 RdRp than remdesivir. Sequences of RdRp from Indian SARS-CoV-2 variants were compared to the original strain from Wuhan, revealing mutations at Y175, W290, Y346, H347, K478, and R583, which changed the structural dynamics as well as intra-atomic interactions. However, none of the mutations appeared at the polyphenol-binding sites, and subsequent docking demonstrated that 10'- Hydroxyusambarensine, Cyanidin-3-arabinoside, Cordifolide A, and Usararotenoid A retained binding affinities comparable to those observed for the wild-type structure. Discussion: The comparatively higher binding affinity of the four polyphenols to RdRp than remdesivir emphasizes their potential as effective antiviral candidates. The absence of mutationinduced alterations in binding sites for the four polyphenols suggests a lower risk of resistance development. These understandings further support in vitro and in vivo assessment of these polyphenols for SARS-CoV-2 therapies. Conclusion: Conservation of RdRp binding sites indicates that the polyphenolic compounds investigated in this study could retain activity against several SARS-CoV-2 variants.