Abrogation of ORF8–IRF3 binding interface with Carbon nanotube derivatives to rescue the host immune system against SARS-CoV-2 by using molecular screening and simulation approaches

Abstract

Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to over six million deaths worldwide. In human immune system, the type 1 interferon (IFN) pathway plays a crucial role in fighting viral infections. However, the ORF8 protein of the virus evade the immune system by interacting with IRF3, hindering its nuclear translocation and consequently downregulate the type I IFN signaling pathway. To block the binding of ORF8–IRF3 and inhibit viral pathogenesis a quick discovery of an inhibitor molecule is needed. Therefore, in the present study, the interface between the ORF8 and IRF3 was targeted on a high-affinity carbon nanotube by using computational tools. After analysis of 62 carbon nanotubes by multiple docking with the induced fit model, the top five compounds with high docking scores of − 7.94 kcal/mol, − 7.92 kcal/mol, − 7.28 kcal/mol, − 7.19 kcal/mol and − 7.09 kcal/mol (top hit1-5) were found to have inhibitory activity against the ORF8–IRF3 complex. Molecular dynamics analysis of the complexes revealed the high compactness of residues, stable binding, and strong hydrogen binding network among the ORF8-nanotubes complexes. Moreover, the total binding free energy for top hit1-5 was calculated to be − 43.21 ± 0.90 kcal/mol, − 41.17 ± 0.99 kcal/mol, − 48.85 ± 0.62 kcal/mol, − 43.49 ± 0.77 kcal/mol, and − 31.18 ± 0.78 kcal/mol respectively. These results strongly suggest that the identified top five nanotubes (hit1-5) possess significant potential for advancing and exploring innovative drug therapies. This underscores their suitability for subsequent in vivo and in vitro experiments, marking them as promising candidates worthy of further investigation.

Keywords

• SARS-CoV-2
• ORF8
• IRF3
• Nanotubes
• Molecular simulation