In Silico Identification of New Anti-SARS-CoV-2 Agents from Bioactive Phytocompounds Targeting the Viral Spike Glycoprotein and Human TLR4

Background: The recent outbreak of novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 has posed a tremendous threat to mankind. The unavailability of a specific drug or vaccine has been the major concern to date. Spike (S) glycoprotein of SARS-CoV-2 plays the most crucial role in viral infection and immunopathogenesis, and hence this protein appears to be an efficacious target for drug discovery. Objective: The objective of this study was to identify potent bioactive phytocompound that can target viral spike (S) glycoprotein and human TLR4 to reduce immunopathological manifestations of COVID- 19. Methods: A series of thirty (30) bioactive phytocompounds, previously documented for antiviral activity, were theoretically screened for their binding efficacy against key proteins related to the pathogenesis of SARS-CoV-2, namely viral spike (S) glycoprotein, and human TLR4. MD simulation was employed to verify the postulations of molecular docking study, and further ADME analysis was performed to predict the most effective one. Results: Studies hypothesized that two new phytochemicals, viz. cajaninstilbene acid (-8.83 kcal/mol) and papaverine (-5.81 kcal/mol), might be the potent inhibitors of spike glycoprotein with stout binding affinity and favourable ADME attributes. MD simulation further ratified the stability of the docked complexes between the phytochemicals and S protein through strong hydrogen bonding. Our In Silico data also indicated that cajaninstilbene acid and papaverine might block human TLR4, which could be useful in mitigating SARS-CoV-2-induced lethal proinflammatory responses. Conclusion: Experimental data collectively predict cajaninstilbene acid as the potential blocker of S protein which may be used as an anti-viral against COVID-19 in the future. However, further experimental validations alongside toxicological detailing are needed for claiming the candidature of these molecules as future anti-corona therapeutics.