Advanced Computational Approaches to Evaluate the Potential of New-Generation Adamantane-Based Drugs as Viroporin...

Traditional adamantane derivatives have demonstrated potential in inhibiting ion channels and viroporins of influenza A virus. Viroporins are oligomeric viral proteins that form membrane channels, facilitating cation transport across host cell membranes, which are critical for the life cycles of pathogenic viruses. The SARS-CoV-2 E-protein, also a viroporin, plays a crucial role in viral packaging and replication; disrupting its function reduces the viral pathogenicity. This study employs advanced in silico analysis to investigate the efficacy of several new-generation adamantane derivatives against the SARS-CoV-2 E-protein ion channel. We have calculated binding energies using molecular mechanics Poisson-Boltzmann surface area (MMPBSA), and alchemical absolute binding free energy (ABFE) methods. Our results predict that the adamantane-based drugs opaganib, artefenomel, and its regioisomer RLA-3107 exhibit strong affinity and significant inhibitory potential in blocking ion channels, thereby preventing the passage of cations into the host cytoplasm. Our analysis reveals that hydrophobic interactions between the adamantane cage and key Leu residues drive channel closure. The detailed mechanism of these drugs against SARS-CoV-2 viroporin serves as a case study to guide future research on other viroporins.