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Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating effect globally with no effective treatment. The swift strategy to find effective treatment against coronavirus disease 2019 (COVID-19) is to repurpose the approved drugs. In this pursuit, an...

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Autores principales: Rampogu, Shailima, Lee, Keun Woo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141588/
https://www.ncbi.nlm.nih.gov/pubmed/34041221
http://dx.doi.org/10.3389/fchem.2021.636362
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author Rampogu, Shailima
Lee, Keun Woo
author_facet Rampogu, Shailima
Lee, Keun Woo
author_sort Rampogu, Shailima
collection PubMed
description The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating effect globally with no effective treatment. The swift strategy to find effective treatment against coronavirus disease 2019 (COVID-19) is to repurpose the approved drugs. In this pursuit, an exhaustive computational method has been used on the DrugBank compounds targeting nsp16/nsp10 complex (PDB code: 6W4H). A structure-based pharmacophore model was generated, and the selected model was escalated to screen DrugBank database, resulting in three compounds. These compounds were subjected to molecular docking studies at the protein-binding pocket employing the CDOCKER module available with the Discovery Studio v18. In order to discover potential candidate compounds, the co-crystallized compound S-adenosyl methionine (SAM) was used as the reference compound. Additionally, the compounds remdesivir and hydroxycholoroquine were employed for comparative docking. The results have shown that the three compounds have demonstrated a higher dock score than the reference compounds and were upgraded to molecular dynamics simulation (MDS) studies. The MDS results demonstrated that the three compounds, framycetin, kanamycin, and tobramycin, are promising candidate compounds. They have represented a stable binding mode at the targets binding pocket with an average protein backbone root mean square deviation below 0.3 nm. Additionally, they have prompted the hydrogen bonds during the entire simulations, inferring that the compounds have occupied the active site firmly. Taken together, our findings propose framycetin, kanamycin, and tobramycin as potent putative inhibitors for COVID-19 therapeutics.
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spelling pubmed-81415882021-05-25 Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics Rampogu, Shailima Lee, Keun Woo Front Chem Chemistry The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating effect globally with no effective treatment. The swift strategy to find effective treatment against coronavirus disease 2019 (COVID-19) is to repurpose the approved drugs. In this pursuit, an exhaustive computational method has been used on the DrugBank compounds targeting nsp16/nsp10 complex (PDB code: 6W4H). A structure-based pharmacophore model was generated, and the selected model was escalated to screen DrugBank database, resulting in three compounds. These compounds were subjected to molecular docking studies at the protein-binding pocket employing the CDOCKER module available with the Discovery Studio v18. In order to discover potential candidate compounds, the co-crystallized compound S-adenosyl methionine (SAM) was used as the reference compound. Additionally, the compounds remdesivir and hydroxycholoroquine were employed for comparative docking. The results have shown that the three compounds have demonstrated a higher dock score than the reference compounds and were upgraded to molecular dynamics simulation (MDS) studies. The MDS results demonstrated that the three compounds, framycetin, kanamycin, and tobramycin, are promising candidate compounds. They have represented a stable binding mode at the targets binding pocket with an average protein backbone root mean square deviation below 0.3 nm. Additionally, they have prompted the hydrogen bonds during the entire simulations, inferring that the compounds have occupied the active site firmly. Taken together, our findings propose framycetin, kanamycin, and tobramycin as potent putative inhibitors for COVID-19 therapeutics. Frontiers Media S.A. 2021-05-10 /pmc/articles/PMC8141588/ /pubmed/34041221 http://dx.doi.org/10.3389/fchem.2021.636362 Text en Copyright © 2021 Rampogu and Lee. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Rampogu, Shailima
Lee, Keun Woo
Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics
title Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics
title_full Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics
title_fullStr Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics
title_full_unstemmed Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics
title_short Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics
title_sort pharmacophore modelling-based drug repurposing approaches for sars-cov-2 therapeutics
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141588/
https://www.ncbi.nlm.nih.gov/pubmed/34041221
http://dx.doi.org/10.3389/fchem.2021.636362
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