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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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