SARS-CoV-2 encodes eight accessory proteins, one of which, ORF8, has a poorly conserved sequence with SARS-CoV and its role in viral pathogenicity has recently been identified. ORF8 in SARS-CoV-2 has a unique functional feature that allows it to form a dimer structure linked by a disulfide bridge between Cys20 and Cys20 (S-S). This study provides structural characterization of natural mutant variants as well as the identification of potential drug candidates capable of binding directly to the interchain disulfide bridge. The lead compounds reported in this work have a tendency to settle in the dimeric interfaces by direct interaction with the disulfide bridge. These molecules may disturb the dimer formation and may have an inhibition impact on its potential functional role in host immune evasion and virulence pathogenicity. This work provides detailed insights on the sequence and structural variability through computational mutational studies, as well as potent drug candidates with the ability to interrupt the intermolecular disulfide bridge formed between Cys20 and Cys20. Furthermore, the interactions of ORF8 peptides complexed with MHC-1 is studied, and the binding mode reveals that certain ORF8 peptides bind to MHC-1 in a manner similar to other viral peptides. Overall, this study is a narrative of various computational approaches used to provide detailed structural insights into SARS-CoV-2 ORF8 interchain disulfide bond disruptors.

Computer Aided Drug Design and Molecular Modeling Lab Department of Bioinformatics Science Block Alagappa University Karaikudi Tamil Nādu 630004 India

Department of Biology College of Science in Zulfi Majmaah University Majmaah 11952 Saudi Arabia

Division of Research and Innovation Saveetha School of Engineering SIMATS Chennai 602105 India

Institute of Biostructures and Bioimaging National Research Council Via Mezzocannone 16 Naples 80134 Italy

Institute of Organic Chemistry and Biochemistry AS CR v v i Flemingovo nam 2 16610 Prague 6 Czechia

Citace poskytuje Crossref.org