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Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach
The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibit...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414997/ https://www.ncbi.nlm.nih.gov/pubmed/36015134 http://dx.doi.org/10.3390/ph15080986 |
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author | Osorio, Manuel I. Yáñez, Osvaldo Gallardo, Mauricio Zuñiga-Bustos, Matías Mulia-Rodríguez, Jorge López-Rendón, Roberto García-Beltrán, Olimpo González-Nilo, Fernando Pérez-Donoso, José M. |
author_facet | Osorio, Manuel I. Yáñez, Osvaldo Gallardo, Mauricio Zuñiga-Bustos, Matías Mulia-Rodríguez, Jorge López-Rendón, Roberto García-Beltrán, Olimpo González-Nilo, Fernando Pérez-Donoso, José M. |
author_sort | Osorio, Manuel I. |
collection | PubMed |
description | The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design. |
format | Online Article Text |
id | pubmed-9414997 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94149972022-08-27 Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach Osorio, Manuel I. Yáñez, Osvaldo Gallardo, Mauricio Zuñiga-Bustos, Matías Mulia-Rodríguez, Jorge López-Rendón, Roberto García-Beltrán, Olimpo González-Nilo, Fernando Pérez-Donoso, José M. Pharmaceuticals (Basel) Article The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design. MDPI 2022-08-11 /pmc/articles/PMC9414997/ /pubmed/36015134 http://dx.doi.org/10.3390/ph15080986 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Osorio, Manuel I. Yáñez, Osvaldo Gallardo, Mauricio Zuñiga-Bustos, Matías Mulia-Rodríguez, Jorge López-Rendón, Roberto García-Beltrán, Olimpo González-Nilo, Fernando Pérez-Donoso, José M. Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach |
title | Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach |
title_full | Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach |
title_fullStr | Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach |
title_full_unstemmed | Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach |
title_short | Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach |
title_sort | search for novel potent inhibitors of the sars-cov-2 papain-like enzyme: a computational biochemistry approach |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414997/ https://www.ncbi.nlm.nih.gov/pubmed/36015134 http://dx.doi.org/10.3390/ph15080986 |
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