Cargando…

Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus

The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O-methyltransferase (nsp16) enzyme that is cruci...

Descripción completa

Detalles Bibliográficos
Autores principales: Sulimov, Alexey, Kutov, Danil, Ilin, Ivan, Xiao, Yibei, Jiang, Sheng, Sulimov, Vladimir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100384/
https://www.ncbi.nlm.nih.gov/pubmed/35566072
http://dx.doi.org/10.3390/molecules27092721
_version_ 1784706839076667392
author Sulimov, Alexey
Kutov, Danil
Ilin, Ivan
Xiao, Yibei
Jiang, Sheng
Sulimov, Vladimir
author_facet Sulimov, Alexey
Kutov, Danil
Ilin, Ivan
Xiao, Yibei
Jiang, Sheng
Sulimov, Vladimir
author_sort Sulimov, Alexey
collection PubMed
description The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O-methyltransferase (nsp16) enzyme that is crucial for effective translation of viral RNA and virus replication. For methylation of substrates, nsp16 utilizes S-adenosyl methionine (SAM). Binding of a small molecule in the protein site where SAM binds can disrupt the synthesis of viral proteins and, as a result, the replication of the virus. Here, we performed high-throughput docking into the SAM-binding site of nsp16 for almost 40 thousand structures, prepared for compounds from three libraries: Enamine Coronavirus Library, Enamine Nucleoside Mimetics Library, and Chemdiv Nucleoside Analogue Library. For the top scoring ligands, semi-empirical quantum-chemical calculations were performed, to better estimate protein–ligand binding enthalpy. Relying upon the calculated binding energies and predicted docking poses, we selected 21 compounds for experimental testing.
format Online
Article
Text
id pubmed-9100384
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91003842022-05-14 Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus Sulimov, Alexey Kutov, Danil Ilin, Ivan Xiao, Yibei Jiang, Sheng Sulimov, Vladimir Molecules Article The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O-methyltransferase (nsp16) enzyme that is crucial for effective translation of viral RNA and virus replication. For methylation of substrates, nsp16 utilizes S-adenosyl methionine (SAM). Binding of a small molecule in the protein site where SAM binds can disrupt the synthesis of viral proteins and, as a result, the replication of the virus. Here, we performed high-throughput docking into the SAM-binding site of nsp16 for almost 40 thousand structures, prepared for compounds from three libraries: Enamine Coronavirus Library, Enamine Nucleoside Mimetics Library, and Chemdiv Nucleoside Analogue Library. For the top scoring ligands, semi-empirical quantum-chemical calculations were performed, to better estimate protein–ligand binding enthalpy. Relying upon the calculated binding energies and predicted docking poses, we selected 21 compounds for experimental testing. MDPI 2022-04-23 /pmc/articles/PMC9100384/ /pubmed/35566072 http://dx.doi.org/10.3390/molecules27092721 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
Sulimov, Alexey
Kutov, Danil
Ilin, Ivan
Xiao, Yibei
Jiang, Sheng
Sulimov, Vladimir
Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
title Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
title_full Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
title_fullStr Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
title_full_unstemmed Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
title_short Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
title_sort novel inhibitors of 2′-o-methyltransferase of the sars-cov-2 coronavirus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100384/
https://www.ncbi.nlm.nih.gov/pubmed/35566072
http://dx.doi.org/10.3390/molecules27092721
work_keys_str_mv AT sulimovalexey novelinhibitorsof2omethyltransferaseofthesarscov2coronavirus
AT kutovdanil novelinhibitorsof2omethyltransferaseofthesarscov2coronavirus
AT ilinivan novelinhibitorsof2omethyltransferaseofthesarscov2coronavirus
AT xiaoyibei novelinhibitorsof2omethyltransferaseofthesarscov2coronavirus
AT jiangsheng novelinhibitorsof2omethyltransferaseofthesarscov2coronavirus
AT sulimovvladimir novelinhibitorsof2omethyltransferaseofthesarscov2coronavirus