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In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations

In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible...

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Autores principales: El Hassab, Mahmoud A., Ibrahim, Tamer M., Shoun, Aly A., Al-Rashood, Sara T., Alkahtani, Hamad M., Alharbi, Amal, Eskandrani, Razan O., Eldehna, Wagdy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029993/
https://www.ncbi.nlm.nih.gov/pubmed/35481212
http://dx.doi.org/10.1039/d1ra01809d
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author El Hassab, Mahmoud A.
Ibrahim, Tamer M.
Shoun, Aly A.
Al-Rashood, Sara T.
Alkahtani, Hamad M.
Alharbi, Amal
Eskandrani, Razan O.
Eldehna, Wagdy M.
author_facet El Hassab, Mahmoud A.
Ibrahim, Tamer M.
Shoun, Aly A.
Al-Rashood, Sara T.
Alkahtani, Hamad M.
Alharbi, Amal
Eskandrani, Razan O.
Eldehna, Wagdy M.
author_sort El Hassab, Mahmoud A.
collection PubMed
description In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible for the viral RNA protection via a cap formation process. In this study, we propose a new potential inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16). A fragment library was screened against the co-crystal structure of the SARS COV-2 2′-O-methyltransferase complexed with Sinefungin (nsp16 – PDB ID: 6WKQ), and consequently the best proposed fragments were linked via a de novo approach to build molecule AP-20. Molecule AP-20 displayed a superior docking score to Sinefungin and reproduced the key interactions in the binding site of 2′-O-methyltransferase. Three molecular dynamic simulations of the 2′-O-methyltransferase apo structure and its complexed forms with AP-20 and Sinefungin were performed for 150 nano-seconds to provide insights on the dynamic nature of such setups and to assess the stability of the proposed AP-20/enzyme complex. AP-20/enzyme complex demonstrated better stability for the ligand–enzyme complex compared to Sinefungin in a respective setup. Furthermore, MM-PBSA binding free energy calculations showed a better profile for AP-20/enzyme complex compared to Sinefungin/enzyme complex emphasizing the potential inhibitory effect of AP-20 on SARS COV-2 2′-O-methyltransferase. We endorse our designed molecule AP-20 to be further explored via experimental evaluations to confront the spread of the emerging COVID-19. Also, in silico ADME profiling has ascribed to AP-20 an excellent safety and metabolic stability profile.
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spelling pubmed-90299932022-04-26 In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations El Hassab, Mahmoud A. Ibrahim, Tamer M. Shoun, Aly A. Al-Rashood, Sara T. Alkahtani, Hamad M. Alharbi, Amal Eskandrani, Razan O. Eldehna, Wagdy M. RSC Adv Chemistry In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible for the viral RNA protection via a cap formation process. In this study, we propose a new potential inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16). A fragment library was screened against the co-crystal structure of the SARS COV-2 2′-O-methyltransferase complexed with Sinefungin (nsp16 – PDB ID: 6WKQ), and consequently the best proposed fragments were linked via a de novo approach to build molecule AP-20. Molecule AP-20 displayed a superior docking score to Sinefungin and reproduced the key interactions in the binding site of 2′-O-methyltransferase. Three molecular dynamic simulations of the 2′-O-methyltransferase apo structure and its complexed forms with AP-20 and Sinefungin were performed for 150 nano-seconds to provide insights on the dynamic nature of such setups and to assess the stability of the proposed AP-20/enzyme complex. AP-20/enzyme complex demonstrated better stability for the ligand–enzyme complex compared to Sinefungin in a respective setup. Furthermore, MM-PBSA binding free energy calculations showed a better profile for AP-20/enzyme complex compared to Sinefungin/enzyme complex emphasizing the potential inhibitory effect of AP-20 on SARS COV-2 2′-O-methyltransferase. We endorse our designed molecule AP-20 to be further explored via experimental evaluations to confront the spread of the emerging COVID-19. Also, in silico ADME profiling has ascribed to AP-20 an excellent safety and metabolic stability profile. The Royal Society of Chemistry 2021-04-29 /pmc/articles/PMC9029993/ /pubmed/35481212 http://dx.doi.org/10.1039/d1ra01809d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
El Hassab, Mahmoud A.
Ibrahim, Tamer M.
Shoun, Aly A.
Al-Rashood, Sara T.
Alkahtani, Hamad M.
Alharbi, Amal
Eskandrani, Razan O.
Eldehna, Wagdy M.
In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations
title In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations
title_full In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations
title_fullStr In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations
title_full_unstemmed In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations
title_short In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations
title_sort in silico identification of potential sars cov-2 2′-o-methyltransferase inhibitor: fragment-based screening approach and mm-pbsa calculations
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029993/
https://www.ncbi.nlm.nih.gov/pubmed/35481212
http://dx.doi.org/10.1039/d1ra01809d
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