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Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface

After over two years of living with Covid-19 and hundreds of million cases worldwide there is still an unmet need to find proper treatments for the novel coronavirus, due also to the rapid mutation of its genome. In this context, a drug repositioning study has been performed, using in silico tools t...

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Autores principales: Pirolli, Davide, Righino, Benedetta, Camponeschi, Chiara, Ria, Francesco, Di Sante, Gabriele, De Rosa, Maria Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9880937/
https://www.ncbi.nlm.nih.gov/pubmed/36707679
http://dx.doi.org/10.1038/s41598-023-28716-8
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author Pirolli, Davide
Righino, Benedetta
Camponeschi, Chiara
Ria, Francesco
Di Sante, Gabriele
De Rosa, Maria Cristina
author_facet Pirolli, Davide
Righino, Benedetta
Camponeschi, Chiara
Ria, Francesco
Di Sante, Gabriele
De Rosa, Maria Cristina
author_sort Pirolli, Davide
collection PubMed
description After over two years of living with Covid-19 and hundreds of million cases worldwide there is still an unmet need to find proper treatments for the novel coronavirus, due also to the rapid mutation of its genome. In this context, a drug repositioning study has been performed, using in silico tools targeting Delta Spike protein/ACE2 interface. To this aim, it has been virtually screened a library composed by 4388 approved drugs through a deep learning-based QSAR model to identify protein–protein interactions modulators for molecular docking against Spike receptor binding domain (RBD). Binding energies of predicted complexes were calculated by Molecular Mechanics/Generalized Born Surface Area from docking and molecular dynamics simulations. Four out of the top twenty ranking compounds showed stable binding modes on Delta Spike RBD and were evaluated also for their effectiveness against Omicron. Among them an antihistaminic drug, fexofenadine, revealed very low binding energy, stable complex, and interesting interactions with Delta Spike RBD. Several antihistaminic drugs were found to exhibit direct antiviral activity against SARS-CoV-2 in vitro, and their mechanisms of action is still debated. This study not only highlights the potential of our computational methodology for a rapid screening of variant-specific drugs, but also represents a further tool for investigating properties and mechanisms of selected drugs.
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spelling pubmed-98809372023-01-27 Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface Pirolli, Davide Righino, Benedetta Camponeschi, Chiara Ria, Francesco Di Sante, Gabriele De Rosa, Maria Cristina Sci Rep Article After over two years of living with Covid-19 and hundreds of million cases worldwide there is still an unmet need to find proper treatments for the novel coronavirus, due also to the rapid mutation of its genome. In this context, a drug repositioning study has been performed, using in silico tools targeting Delta Spike protein/ACE2 interface. To this aim, it has been virtually screened a library composed by 4388 approved drugs through a deep learning-based QSAR model to identify protein–protein interactions modulators for molecular docking against Spike receptor binding domain (RBD). Binding energies of predicted complexes were calculated by Molecular Mechanics/Generalized Born Surface Area from docking and molecular dynamics simulations. Four out of the top twenty ranking compounds showed stable binding modes on Delta Spike RBD and were evaluated also for their effectiveness against Omicron. Among them an antihistaminic drug, fexofenadine, revealed very low binding energy, stable complex, and interesting interactions with Delta Spike RBD. Several antihistaminic drugs were found to exhibit direct antiviral activity against SARS-CoV-2 in vitro, and their mechanisms of action is still debated. This study not only highlights the potential of our computational methodology for a rapid screening of variant-specific drugs, but also represents a further tool for investigating properties and mechanisms of selected drugs. Nature Publishing Group UK 2023-01-27 /pmc/articles/PMC9880937/ /pubmed/36707679 http://dx.doi.org/10.1038/s41598-023-28716-8 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Pirolli, Davide
Righino, Benedetta
Camponeschi, Chiara
Ria, Francesco
Di Sante, Gabriele
De Rosa, Maria Cristina
Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface
title Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface
title_full Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface
title_fullStr Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface
title_full_unstemmed Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface
title_short Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface
title_sort virtual screening and molecular dynamics simulations provide insight into repurposing drugs against sars-cov-2 variants spike protein/ace2 interface
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9880937/
https://www.ncbi.nlm.nih.gov/pubmed/36707679
http://dx.doi.org/10.1038/s41598-023-28716-8
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