{"doi":"10.1016/j.csbj.2025.06.036","title":"<i>In silico</i> determination of novel SARS-CoV-2 envelope protein ion channel inhibitors","abstract":"<h2>Abstract</h2> The SARS-CoV-2 envelope protein (2-E<sup>PRO</sup>), 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<sup>PRO</sup> 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<sup>PRO</sup> 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.","journal":"Computational and Structural Biotechnology Journal","year":2025,"id":544981,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1435861,"name":"Lennart Dreisewerd","orcid":null,"position":1,"is_corresponding":false},{"id":1435422,"name":"Matic Pavlin","orcid":"0000-0003-4354-3438","position":2,"is_corresponding":false},{"id":1435423,"name":"Polona Kogovšek","orcid":"0000-0002-4035-0115","position":3,"is_corresponding":false},{"id":1435424,"name":"Črtomir Podlipnik","orcid":"0000-0002-8429-0273","position":4,"is_corresponding":false},{"id":1435425,"name":"Uroš Grošelj","orcid":"0000-0002-5186-9879","position":5,"is_corresponding":false},{"id":504678,"name":"Miha Lukšič","orcid":"0000-0001-7190-4013","position":6,"is_corresponding":false},{"id":1435860,"name":"Nina Kobe","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:53:17.418915Z","pmid":"40677240","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}