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.

Toll-Like Receptors (TLRs) as Therapeutic Targets for Treating SARS-CoV-2: An Immunobiological Perspective.

INTRODUCTION: Coronavirus disease-19 (COVID-19) caused by SARS-CoV-2 is presently the biggest threat to mankind throughout the globe. Increasing reports on deaths, cases of new infection, and socioeconomic losses are continuously coming from all parts of the world. Developing an efficacious drug and/or vaccine is currently the major goal to the scientific communities. In this context, toll-like receptors (TLRs) could be the useful targets in adopting effective therapeutic approaches. METHODS: This chapter has been written by incorporating the findings on TLR-based therapies against SARS-CoV-2 demonstrated in the recently published research papers/reviews. RESULTS: TLRs are the essential components of host immunity and play critical roles in deciding the fate of SARS-CoV-2 by influencing the immunoregulatory circuits governing human immune response to this pathogen. Hitherto, a number of multi-subunit peptide-based vaccines and pharmacological agents developed against SARS-CoV-2 have been found to manipulate TLR function. Therefore, circumventing overt immunopathology of COVID-19 applying TLR-antagonists can effectively reduce the morality caused from "cytokine storm"-induced multiorgan failure. Similarly, pre-administration of TLR- agonists may be used as a prophylaxis to sensitize the immune system of the individuals having risk of infection. A lot of collaborative efforts are required for bench-to-bench transformation of these knowledges. CONCLUSION: This chapter enlightens the potentials and promises of TLR-guided therapeutic strategies against COVID-19 by reviewing the major findings and achievements depicted in the literatures published till date.

In silico analyses on the comparative sensing of SARS-CoV-2 mRNA by the intracellular TLRs of humans.

The coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already resulted in a huge setback to mankind in terms of millions of deaths, while the unavailability of an appropriate therapeutic strategy has made the scenario much more severe. Toll-like receptors (TLRs) are crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS-CoV-2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3, 7, 8, and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing pro-inflammatory responses in COVID-19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study hopes to rationalize the comparative binding of the major SARS-CoV-2 mRNAs to the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are possible virus-associated molecular patterns that bind to TLR3, TLR9, and TLR7, respectively, and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand-binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is the maiden report to describe the role of TLR3, 7, and 9 in COVID-19 immunobiology and these could serve as useful targets for the conception of a therapeutic strategy against the pandemic.

Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an <i>in silico</i> approach

Aim: COVID-19 is currently the biggest threat to mankind. Recently, ivermectin (a US FDA-approved antiparasitic drug) has been explored as an anti-SARS-CoV-2 agent. Herein, we have studied the possible mechanism of action of ivermectin using in silico approaches. Materials &methods: Interaction of ivermectin against the key proteins involved in SARS-CoV-2 pathogenesis were investigated through molecular docking and molecular dynamic simulation. Results: Ivermectin was found as a blocker of viral replicase, protease and human TMPRSS2, which could be the biophysical basis behind its antiviral efficiency. The antiviral action and ADMET profile of ivermectin was on par with the currently used anticorona drugs such as hydroxychloroquine and remdesivir. Conclusion: Our study enlightens the candidature of ivermectin as an effective drug for treating COVID-19.</p>