Exploring polyamine interactions and binding pockets in SARS-CoV-2 ORF3a

• Published in: Journal of molecular graphics & modelling 2023-07, Vol.122, p.108487-108487, Article 108487
• Main Authors: Boonamnaj, Panisak, Pandey, R.B., Sompornpisut, Pornthep
• Format: Article
• Language: English
• Subjects: COVID-19; COVID-19 Drug Treatment; Humans; Ligands; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Open Reading Frames; ORF3a; Polyamines; SAR-CoV-2; SARS-CoV-2; Spermidine
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2023.108487

Ongoing global pandemic caused by coronavirus (COVID-19) requires urgent development of vaccines, treatments, and diagnostic tools. Open reading frame 3a (ORF3a) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered to be a potential drug target for COVID-19 treatment. ORF3a is an accessory protein that plays a significant role in virus-host interactions and in facilitating host immune responses. Using putrescine, spermidine and spermine, an aliphatic polyamine for the activity suppression of ORF3a appears to be a promising approach in finding new targets for drug design. In this study, we explored the possible binding poses of polyamines to the ORF3a protein using a combination of various computational approaches i.e. pocket prediction, blind and site-specific molecular docking, molecular dynamics and ligand flooding simulations. The results showed that the tip of cytoplasmic domain and the upper tunnel of transmembrane domain of ORF3a provide a suitable binding site specific for the polyamines. MD simulations revealed the stability of spermidine binding in the upper tunnel pocket of ORF3a through salt bridge and hydrogen bond interactions between the amine groups of the ligand and negatively charged residues of ORF3a. These findings can be helpful in designing new therapeutic drugs. [Display omitted] •The discovery of possible inhibitors of SARS-CoV-2 is extremely important.•ORF3a is a potential target for the development of treatments against COVID-19.•Exploring interactions for polyamines in ORF3a through computational techniques.•The upper tunnel of ORF3a could potentially act as a binding pocket for spermidine.