In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors

The SARS-CoV-2 envelope protein (2-E^PRO), a viroporin crucial for viral pathogenesis, is a promising target for antiviral drug development as it is highly conserved and functionally important. Although it is a promising therapeutic target for the treatment of COVID-19, it has often been overlooked in previous studies. In this study, a high-throughput virtual screening of nearly one billion compounds was performed, followed by rigorous filtering and re-docking. Eight best-scoring and chemically versatile lead candidates were identified. In molecular dynamics simulations, three of these ligands showed stable protein-ligand complexes occupying the 2-E^PRO channel pore. Among these, ZINC001799167680 (L3) and ZINC001081252239 (L2) exhibited the strongest binding affinity, with key interactions at residues ASN15, THR11 and GLU8 identified by Molecular Mechanics Poisson-Boltzmann Surface Area analysis. All ligands were compared with the known inhibitor rimantadine and showed stronger binding to the protein. These <i>in silico</i> results highlight the potential of focusing on the 2-E^PRO ion channel in the development of novel COVID-19 therapeutics and pave the way for further <i>in vitro</i> and <i>in vivo</i> studies.