In silico screening, ADMET analysis, MD simulations, and MM/PBSA binding free energy identify new inhibitor molecules for viroporin E

Vaccine technology enabled the rapid development and approval of COVID-19 vaccines, whereas antiviral treatments for SARS-CoV-2 often rely on existing drugs. One treatment method involves creating antiviral molecules that target the virus's structural proteins, which are essential to its lifecycle. Many antiviral agents focus on spike, membrane, and nucleocapsid proteins, but the envelope protein has been less studied. The envelope protein has a low mutation rate, is conserved across variants, and differs from human ion channels, suggesting it could be an effective drug target.This study sought to identify antiviral molecules targeting the viroporin E lumen by screening 6,287 compounds from the ASINEX antiviral library using virtual screening. Eleven known viroporin E inhibitors were used as controls. Docking was done using popular programs with an NMR-resolved viroporin structure. Eight ASINEX compounds were identified as promising inhibitors based on their docking scores and interactions with the viroporin E channel. All compounds showed good ADMET properties and stability at the binding site in molecular dynamics simulations and MM-PBSA analyses. The ProTox-III evaluation also indicated that these compounds have a safer metabolic profile than natural controls, suggesting their potential as viroporin E inhibitors.