Integration of metabolomics and chemometrics with in-silico and in-vitro approaches to unravel SARS-Cov-2 inhibitors from South African plants

Coronavirus disease (COVID-19) is still a severe concern, especially in Africa with suboptimal intention rates of vaccination. This flagged the requirement of plant-based remedies as an alternative treatment. In this study we integrated metabolomics and chemometrics approaches with In silico and In vitro approaches to accelerate and unravel compounds from commonly used South African plants that may inhibit SARS-CoV-2 main protease. The selected commonly used plants, Artemisia afra and Artemisia annua, were found to be non-toxic against Vero cells, as determined by the resazurin cell viability assay. Metabolites profiling revealed eighty-one compounds and the top three hit compounds, quercetin 3-O-(6"-acetyl-glucoside), 2"-O-acetylrutin, and quercetin 3-(6"-malonyl-glucoside), had binding affinities of -9.3 kcal/mol, -9.5 kcal/mol, and -9.3 kcal/mol, respectively. The 2"-O-acetyl group of the rutin moiety and quercetin moiety produces a hydrogen bond with the amide nitrogen of His41 and with the side chain carboxylate of Cys145, respectively. Molecular dynamics simulations revealed a stable binding of the docked complexes. In silico observations were validated by In vitro bioassay, which flagged the ability of these compounds to inhibit SARS-CoV-2 3CLpro. The collected analysed data of this study does not only draw special attention to the surfaced 2"-O-acetylrutin as the best suitable inhibitor of SARS-CoV-2 3CLpro, but also indirectly reveals the importance of integrating metabolomics and chemometrics approaches with In silico and In vitro approaches to accelerate and unravel compounds from South African commonly used plants.