In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors
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 i...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037025002557 |
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| author | Nina Kobe Lennart Dreisewerd Matic Pavlin Polona Kogovšek Črtomir Podlipnik Uroš Grošelj Miha Lukšič |
| author_facet | Nina Kobe Lennart Dreisewerd Matic Pavlin Polona Kogovšek Črtomir Podlipnik Uroš Grošelj Miha Lukšič |
| author_sort | Nina Kobe |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ab04f54863e6480983121c6f77a25df2 |
| institution | Kabale University |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-ab04f54863e6480983121c6f77a25df22025-08-20T03:28:38ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-01272823283110.1016/j.csbj.2025.06.036In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitorsNina Kobe0Lennart Dreisewerd1Matic Pavlin2Polona Kogovšek3Črtomir Podlipnik4Uroš Grošelj5Miha Lukšič6National Institute of Biology, Department of Biotechnology and Systems Biology, Večna pot 121, Ljubljana, SI-1000, Slovenia; Jožef Stefan International Postgraduate School, Jamova cesta 39, Ljubljana, SI-1000, SloveniaUniversity of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, Ljubljana, SI-1000, Slovenia; National Institute of Chemistry, Department of Catalysis and Chemical Reaction Engineering, Hajdrihova 19, Ljubljana, SI-1000, SloveniaNational Institute of Chemistry, Department of Catalysis and Chemical Reaction Engineering, Hajdrihova 19, Ljubljana, SI-1000, Slovenia; Faculty of Polymer Technology, Ozare 19, Slovenj Gradec, SI-2380, SloveniaNational Institute of Biology, Department of Biotechnology and Systems Biology, Večna pot 121, Ljubljana, SI-1000, SloveniaUniversity of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, Ljubljana, SI-1000, SloveniaUniversity of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, Ljubljana, SI-1000, SloveniaUniversity of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, Ljubljana, SI-1000, Slovenia; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2001037025002557SARS-CoV-2 envelope proteinViroporinIon channelChannel blockersMolecular dynamics simulationsFree energy calculations |
| spellingShingle | Nina Kobe Lennart Dreisewerd Matic Pavlin Polona Kogovšek Črtomir Podlipnik Uroš Grošelj Miha Lukšič In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors Computational and Structural Biotechnology Journal SARS-CoV-2 envelope protein Viroporin Ion channel Channel blockers Molecular dynamics simulations Free energy calculations |
| title | In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors |
| title_full | In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors |
| title_fullStr | In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors |
| title_full_unstemmed | In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors |
| title_short | In silico determination of novel SARS-CoV-2 envelope protein ion channel inhibitors |
| title_sort | in silico determination of novel sars cov 2 envelope protein ion channel inhibitors |
| topic | SARS-CoV-2 envelope protein Viroporin Ion channel Channel blockers Molecular dynamics simulations Free energy calculations |
| url | http://www.sciencedirect.com/science/article/pii/S2001037025002557 |
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