Cargando…

Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2

Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. I...

Descripción completa

Detalles Bibliográficos
Autores principales: Nakayoshi, Tomoki, Kato, Koichi, Kurimoto, Eiji, Oda, Akifumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466562/
https://www.ncbi.nlm.nih.gov/pubmed/34576002
http://dx.doi.org/10.3390/ijms22189837
_version_ 1784573172791640064
author Nakayoshi, Tomoki
Kato, Koichi
Kurimoto, Eiji
Oda, Akifumi
author_facet Nakayoshi, Tomoki
Kato, Koichi
Kurimoto, Eiji
Oda, Akifumi
author_sort Nakayoshi, Tomoki
collection PubMed
description Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. In this study, with the structure of the SARS-CoV-2 Mpro complexed with a non-covalent inhibitor, we performed molecular dynamics (MD) simulations to determine the conformation of the complex when single amino acid residue in the active site is mutated. As a model of amino acid mutation, we constructed mutant proteins with one residue in the active site mutated to alanine. This method is called virtual alanine scan. The results of the MD simulations showed that the conformation and configuration of the ligand was changed for mutants H163A and E166A, although the structure of the whole protein and of the catalytic dyad did not change significantly, suggesting that mutations in His163 and Glu166 may be linked to drug resistance.
format Online
Article
Text
id pubmed-8466562
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-84665622021-09-27 Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2 Nakayoshi, Tomoki Kato, Koichi Kurimoto, Eiji Oda, Akifumi Int J Mol Sci Article Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. In this study, with the structure of the SARS-CoV-2 Mpro complexed with a non-covalent inhibitor, we performed molecular dynamics (MD) simulations to determine the conformation of the complex when single amino acid residue in the active site is mutated. As a model of amino acid mutation, we constructed mutant proteins with one residue in the active site mutated to alanine. This method is called virtual alanine scan. The results of the MD simulations showed that the conformation and configuration of the ligand was changed for mutants H163A and E166A, although the structure of the whole protein and of the catalytic dyad did not change significantly, suggesting that mutations in His163 and Glu166 may be linked to drug resistance. MDPI 2021-09-11 /pmc/articles/PMC8466562/ /pubmed/34576002 http://dx.doi.org/10.3390/ijms22189837 Text en © 2021 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
Nakayoshi, Tomoki
Kato, Koichi
Kurimoto, Eiji
Oda, Akifumi
Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2
title Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2
title_full Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2
title_fullStr Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2
title_full_unstemmed Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2
title_short Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2
title_sort virtual alanine scan of the main protease active site in severe acute respiratory syndrome coronavirus 2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466562/
https://www.ncbi.nlm.nih.gov/pubmed/34576002
http://dx.doi.org/10.3390/ijms22189837
work_keys_str_mv AT nakayoshitomoki virtualalaninescanofthemainproteaseactivesiteinsevereacuterespiratorysyndromecoronavirus2
AT katokoichi virtualalaninescanofthemainproteaseactivesiteinsevereacuterespiratorysyndromecoronavirus2
AT kurimotoeiji virtualalaninescanofthemainproteaseactivesiteinsevereacuterespiratorysyndromecoronavirus2
AT odaakifumi virtualalaninescanofthemainproteaseactivesiteinsevereacuterespiratorysyndromecoronavirus2