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Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain

[Image: see text] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic. Several variants of SARS-CoV-2 have emerged worldwide. These variants show different transmissibility infectivity due to mutations in the viral spike (S) gl...

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Autores principales: Rodríguez, Yoel, Cardoze, Scarlet Martínez, Obineche, Onyinyechi W., Melo, Claudia, Persaud, Ashanna, Fernández Romero, José A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380817/
https://www.ncbi.nlm.nih.gov/pubmed/35991504
http://dx.doi.org/10.1021/acsomega.2c00844
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author Rodríguez, Yoel
Cardoze, Scarlet Martínez
Obineche, Onyinyechi W.
Melo, Claudia
Persaud, Ashanna
Fernández Romero, José A.
author_facet Rodríguez, Yoel
Cardoze, Scarlet Martínez
Obineche, Onyinyechi W.
Melo, Claudia
Persaud, Ashanna
Fernández Romero, José A.
author_sort Rodríguez, Yoel
collection PubMed
description [Image: see text] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic. Several variants of SARS-CoV-2 have emerged worldwide. These variants show different transmissibility infectivity due to mutations in the viral spike (S) glycoprotein that interacts with the human angiotensin-converting enzyme 2 (hACE2) receptor and facilitates viral entry into target cells. Despite the effective SARS-CoV-2 vaccines, we still need to identify selective antivirals, and the S glycoprotein is a key target to neutralize the virus. We hypothesize that small molecules could disrupt the interaction of S glycoprotein with hACE2 and inhibit viral entry. We analyzed the S glycoprotein-hACE2 complex structure (PDB: 7DF4) and created models for different viral variants using visual molecular dynamics (VMD) and molecular operating environment (MOE) programs. Moreover, we started the hits search by performing structure-based molecular docking virtual screening of commercially available small molecules against S glycoprotein models using OEDocking FRED-4.0.0.0 software. The FRED-4.0.0.0 Chemguass4 scoring function was used to rank the small molecules based on their affinities. The best candidate compounds were purchased and tested using a standard SARS-CoV-2 pseudotyped cell-based bioassay to investigate their antiviral activity. Three of these compounds, alone or in combination, showed antiviral selectivity. These small molecules may lead to an effective antiviral treatment or serve as probes to better understand the biology of SARS-CoV-2.
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spelling pubmed-93808172022-08-16 Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain Rodríguez, Yoel Cardoze, Scarlet Martínez Obineche, Onyinyechi W. Melo, Claudia Persaud, Ashanna Fernández Romero, José A. ACS Omega [Image: see text] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic. Several variants of SARS-CoV-2 have emerged worldwide. These variants show different transmissibility infectivity due to mutations in the viral spike (S) glycoprotein that interacts with the human angiotensin-converting enzyme 2 (hACE2) receptor and facilitates viral entry into target cells. Despite the effective SARS-CoV-2 vaccines, we still need to identify selective antivirals, and the S glycoprotein is a key target to neutralize the virus. We hypothesize that small molecules could disrupt the interaction of S glycoprotein with hACE2 and inhibit viral entry. We analyzed the S glycoprotein-hACE2 complex structure (PDB: 7DF4) and created models for different viral variants using visual molecular dynamics (VMD) and molecular operating environment (MOE) programs. Moreover, we started the hits search by performing structure-based molecular docking virtual screening of commercially available small molecules against S glycoprotein models using OEDocking FRED-4.0.0.0 software. The FRED-4.0.0.0 Chemguass4 scoring function was used to rank the small molecules based on their affinities. The best candidate compounds were purchased and tested using a standard SARS-CoV-2 pseudotyped cell-based bioassay to investigate their antiviral activity. Three of these compounds, alone or in combination, showed antiviral selectivity. These small molecules may lead to an effective antiviral treatment or serve as probes to better understand the biology of SARS-CoV-2. American Chemical Society 2022-08-09 /pmc/articles/PMC9380817/ /pubmed/35991504 http://dx.doi.org/10.1021/acsomega.2c00844 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Rodríguez, Yoel
Cardoze, Scarlet Martínez
Obineche, Onyinyechi W.
Melo, Claudia
Persaud, Ashanna
Fernández Romero, José A.
Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain
title Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain
title_full Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain
title_fullStr Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain
title_full_unstemmed Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain
title_short Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain
title_sort small molecules targeting sars-cov-2 spike glycoprotein receptor-binding domain
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380817/
https://www.ncbi.nlm.nih.gov/pubmed/35991504
http://dx.doi.org/10.1021/acsomega.2c00844
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