Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication. Therefore, the need for the development of potent antivirals is still of importance. In this context, the SARS-CoV-2 main protease (M pro ) is a critical target and numerous clinical trials, predominantly in the private domain, are currently in progress. Here, our aim was to extend our previous studies, with hypericin and cyanidin-3-O-glucoside, as potential inhibitors of the SARS-CoV-2 M pro . Firstly, we performed all-atom microsecond molecular dynamics simulations, which highlight the stability of the ligands in the M pro active site over the duration of the trajectories. We also invoked PELE Monte Carlo simulations which indicate that both hypericin and cyanidin-3-O-glucoside preferentially interact with the M pro active site and known allosteric sites. For further validation, we performed an in vitro enzymatic activity assay that demonstrated that hypericin and cyanidin-3-O-glucoside inhibit M pro activity in a dose-dependent manner at biologically relevant (μM) concentrations. However, both ligands are much less potent than the well-known covalent antiviral GC376, which was used as a positive control in our experiments. Nevertheless, the biologically relevant activity of hypericin and cyanidin-3-O-glucoside is encouraging. In particular, a synthetic version of hypericin has FDA orphan drug designation, which could simplify potential clinical evaluation in the context of COVID-19.
Keywords: COVID-19; Coronavirus; Cyanidin-3-O-glucoside; GC376; Hypericin; Main protease; Molecular modelling; SARS-CoV-2.
【저자키워드】 COVID-19, SARS-CoV-2, coronavirus, main protease, Molecular modelling, Cyanidin-3-O-glucoside, GC376, Hypericin, 【초록키워드】 SARS-CoV-2, coronavirus, Antiviral, COVID-19 pandemic, variants of concern, clinical trials, molecular dynamics, protease, in vitro, severe acute respiratory syndrome Coronavirus, FDA, SARS-CoV-2 main protease, Vaccine hesitancy, stability, clinical evaluation, eradication, molecular, respiratory, inhibitor, Critical, Hypericin, Ligand, Safe, active site, Orphan Drug, Trajectories, acute respiratory syndrome, glucoside, acute respiratory syndrome coronavirus, Previous studies, acute respiratory syndrome coronavirus 2, enzymatic activity, dose-dependent manner, ligands, situation, domain, M pro, Effective vaccines, positive control, concentrations, highlight, performed, was used, caused, inhibit, less, demonstrated, notable, experiments, the SARS-CoV-2, 【제목키워드】 MD simulations, small molecule, Interaction, in vitro activity, the SARS-CoV-2,