Entry-inhibitory role of catechins against SARS-CoV-2 and its UK variant

Abstract

Background

The global pandemic caused by an RNA virus capable of infecting humans and animals, has resulted in millions of deaths worldwide. Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infects the lungs and the gastrointestinal tract to some extent. Rapid structural mutations have increased the virulence and infectivity of the virus drastically. One such mutated strain known as the UK variant has caused many deaths in the United Kingdom.

Hypothesis

Among several indigenous natural ingredients used for prevention and cure of many diseases, the catechins have been reported for their antiviral activity, even against SARS-CoV-2. Characteristic mutations present on the spike protein have presented the newer strain its enhanced infectivity. The spike protein helps the virus bind to ACE2 receptor of the host cell and hence is a drug target. Catechins have been reported for their entry-inhibitory activity against several viruses.

Method

In this study, we performed molecular docking of different catechins with the wild and mutant variants of the spike protein of SARS-CoV-2. The stability of the best docked complexes was validated using molecular dynamics simulation.

Results

The in-silico studies show that the catechins form favourable interactions with the spike protein and can potentially impair its function. Epigallocatechin gallate (EGCG) showed the best binding among the catechins against both the strains. Both the protein-ligand complexes were stable throughout the simulation time frame.

Conclusion

The outcomes should encourage further exploration of the antiviral activity of EGCG against SARS-CoV-2 and its variants.

Graphical abstract

Summary

The UK variant of SARS-CoV-2 has caused a sudden increase in the number of COVID-19 cases. Characteristic point mutations present on the spike protein have made this new strain far more infectious than the wild strain. There are very few reports that have validated the efficiency of vaccines and approved drugs on the mutated strain. Phytoconstituents, specifically catechins have gathered a lot of attention owing to their immunomodulatory and antiviral activity against several viruses. In this manuscript, we screened several natural catechins against the spike proteins of the wild strain of SARS-CoV-2 and VUI 202012/01, commonly known as the UK variant. We used in-silico tools such as molecular docking and molecular dynamics (MD) simulation to study the binding affinities of catechins towards the active binding sites of spike proteins of both the strains. It was found that all the catechins show better binding affinities towards the spike proteins then their native ligands. Hence, catechins can preferentially bind to the protein and form complexes. Among the catechins screened in this study, EGCG showed the highest binding affinity. The complex was formed with several hydrogen bonds, van der Waals interactions, and other hydrophobic bonds. The stability of this complex was validated using MD simulation of 20 ns. The complex of EGCG with both the wild and spike protein was observed to be stable throughout the simulation. These results show that the catechins, especially EGCG, can be developed as entry-inhibitors of SARS-CoV-2 and its variants. Their in-silico activity however needs to be validated in in vitro and in vivo models. Nevertheless, these molecules offer a promising role in the treatment of viral infections like COVID-19. Another drawback of these molecules are their pharmacokinetic properties and poor bioavailability. These need to be improved by developing drug-conjugates and suitable dosage forms.