ABSTRACT
Flavonoids are vital candidates to fight against a wide range of pathogenic microbial infections. Due to their therapeutic potential, many flavonoids from the herbs of traditional medicine systems are now being evaluated as lead compounds to develop potential antimicrobial hits. The emergence of SARS-CoV-2 caused one of the deadliest pandemics that has ever been known to mankind. To date, more than 600 million confirmed cases of SARS-CoV2 infection have been reported worldwide. Situations are worse due to the unavailability of therapeutics to combat the viral disease. Thus, there is an urgent need to develop drugs against SARS-CoV2 and its emerging variants. Here, we have carried out a detailed mechanistic analysis of the antiviral efficacy of flavonoids in terms of their potential targets and structural feature required for exerting their antiviral activity. A catalog of various promising flavonoid compounds has been shown to elicit inhibitory effects against SARS-CoV and MERS-CoV proteases. However, they act in the high-micromolar regime. Thus a proper lead-optimization against the various proteases of SARS-CoV2 can lead to high-affinity SARS-CoV2 protease inhibitors. To enable lead optimization, a quantitative structure-activity relationship (QSAR) analysis has been developed for the flavonoids that have shown antiviral activity against viral proteases of SARS-CoV and MERS-CoV. High sequence similarities between coronavirus proteases enable the applicability of the developed QSAR to SARS-CoV2 proteases inhibitor screening. The detailed mechanistic analysis of the antiviral flavonoids and the developed QSAR models is a step forward toward the development of flavonoid-based therapeutics or supplements to fight against COVID-19.
ABSTRACT
Recent times witnessed an upsurge in the number of COVID19 cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for an approved therapeutic monoclonal antibody. The Q498R RBD mutation observed across all the omicron variants can reduce â¼12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a â¼6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.