Abrogation of ORF8-IRF3 binding interface with Carbon nanotube derivatives to rescue the host immune system against...

Area of Science:

• Computational drug discovery
• Virology
• Immunology

Background:

• The COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of deaths globally.
• The type 1 interferon (IFN) pathway is critical for the human immune response to viral infections.
• SARS-CoV-2 ORF8 protein disrupts this pathway by inhibiting IRF3, hindering the immune response.

Purpose of the Study:

• To identify potential inhibitors of the SARS-CoV-2 ORF8-IRF3 interaction.
• To explore the use of carbon nanotubes as a drug delivery or inhibitory platform.
• To computationally screen and validate candidate molecules for blocking viral pathogenesis.

Main Methods:

• Computational docking of 62 carbon nanotubes against the ORF8-IRF3 complex using an induced fit model.
• Analysis of binding affinity through docking scores and molecular dynamics simulations.
• Calculation of total binding free energy for top-ranked compounds.

Main Results:

• Five carbon nanotubes (hit1-5) demonstrated high inhibitory activity against the ORF8-IRF3 complex, with docking scores ranging from -7.09 to -7.94 kcal/mol.
• Molecular dynamics revealed stable binding, high residue compactness, and strong hydrogen bonding networks for the top nanotube candidates.
• Calculated total binding free energies for the top five nanotubes ranged from -31.18 ± 0.78 to -48.85 ± 0.62 kcal/mol.

Conclusions:

• The identified top five carbon nanotubes exhibit significant potential as inhibitors of the SARS-CoV-2 ORF8-IRF3 interaction.
• These nanotube compounds are promising candidates for further in vitro and in vivo studies to develop novel COVID-19 therapeutics.
• The findings highlight the utility of computational approaches in rapidly discovering potential antiviral agents.