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

## TL;DR

This study identifies potential inhibitors for the SARS-CoV-2 envelope protein ion channel, which could lead to new treatments for COVID-19.

## Contribution

The study presents novel lead compounds identified through virtual screening and molecular dynamics simulations targeting the 2-EPRO ion channel.

## Key findings

- Eight lead candidates were identified from a high-throughput virtual screening of nearly one billion compounds.
- Three ligands formed stable complexes in the 2-EPRO channel pore, with L3 and L2 showing the strongest binding affinity.
- The identified ligands outperformed the known inhibitor rimantadine in binding strength.

## Abstract

The SARS-CoV-2 envelope protein (2-EPRO), 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-EPRO 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 in silico results highlight the potential of focusing on the 2-EPRO ion channel in the development of novel COVID-19 therapeutics and pave the way for further in vitro and in vivo studies.