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Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors
The viral disease dengue is transmitted by the Aedes mosquito and is commonly seen to occur in the tropical and subtropical regions of the world. It is a growing public health concern. To date, other than supportive treatments, there are no specific antiviral treatments to combat the infection. Ther...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996041/ https://www.ncbi.nlm.nih.gov/pubmed/36911525 http://dx.doi.org/10.3389/fmolb.2023.1106128 |
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author | Poola, Anushka A. Prabhu, Prithvi S. Murthy, T. P. Krishna Murahari, Manikanta Krishna, Swati Samantaray, Mahesh Ramaswamy, Amutha |
author_facet | Poola, Anushka A. Prabhu, Prithvi S. Murthy, T. P. Krishna Murahari, Manikanta Krishna, Swati Samantaray, Mahesh Ramaswamy, Amutha |
author_sort | Poola, Anushka A. |
collection | PubMed |
description | The viral disease dengue is transmitted by the Aedes mosquito and is commonly seen to occur in the tropical and subtropical regions of the world. It is a growing public health concern. To date, other than supportive treatments, there are no specific antiviral treatments to combat the infection. Therefore, finding potential compounds that have antiviral activity against the dengue virus is essential. The NS2B-NS3 dengue protease plays a vital role in the replication and viral assembly. If the functioning of this protease were to be obstructed then viral replication would be halted. As a result, this NS2B-NS3 proves to be a promising target in the process of anti-viral drug design. Through this study, we aim to provide suggestions for compounds that may serve as potent inhibitors of the dengue NS2B-NS3 protein. Here, a ligand-based pharmacophore model was generated and the ZINC database was screened through ZINCPharmer to identify molecules with similar features. 2D QSAR model was developed and validated using reported 4-Benzyloxy Phenyl Glycine derivatives and was utilized to predict the IC50 values of unknown compounds. Further, the study is extended to molecular docking to investigate interactions at the active pocket of the target protein. ZINC36596404 and ZINC22973642 showed a predicted pIC50 of 6.477 and 7.872, respectively. They also showed excellent binding with NS3 protease as is evident from their binding energy of −8.3and −8.1 kcal/mol, respectively. ADMET predictionsofcompounds have shown high drug-likeness. Finally, the molecular dynamic simulations integrated with MM-PBSA binding energy calculations confirmedboth identified ZINC compounds as potential hit moleculeswith good stability. |
format | Online Article Text |
id | pubmed-9996041 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99960412023-03-10 Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors Poola, Anushka A. Prabhu, Prithvi S. Murthy, T. P. Krishna Murahari, Manikanta Krishna, Swati Samantaray, Mahesh Ramaswamy, Amutha Front Mol Biosci Molecular Biosciences The viral disease dengue is transmitted by the Aedes mosquito and is commonly seen to occur in the tropical and subtropical regions of the world. It is a growing public health concern. To date, other than supportive treatments, there are no specific antiviral treatments to combat the infection. Therefore, finding potential compounds that have antiviral activity against the dengue virus is essential. The NS2B-NS3 dengue protease plays a vital role in the replication and viral assembly. If the functioning of this protease were to be obstructed then viral replication would be halted. As a result, this NS2B-NS3 proves to be a promising target in the process of anti-viral drug design. Through this study, we aim to provide suggestions for compounds that may serve as potent inhibitors of the dengue NS2B-NS3 protein. Here, a ligand-based pharmacophore model was generated and the ZINC database was screened through ZINCPharmer to identify molecules with similar features. 2D QSAR model was developed and validated using reported 4-Benzyloxy Phenyl Glycine derivatives and was utilized to predict the IC50 values of unknown compounds. Further, the study is extended to molecular docking to investigate interactions at the active pocket of the target protein. ZINC36596404 and ZINC22973642 showed a predicted pIC50 of 6.477 and 7.872, respectively. They also showed excellent binding with NS3 protease as is evident from their binding energy of −8.3and −8.1 kcal/mol, respectively. ADMET predictionsofcompounds have shown high drug-likeness. Finally, the molecular dynamic simulations integrated with MM-PBSA binding energy calculations confirmedboth identified ZINC compounds as potential hit moleculeswith good stability. Frontiers Media S.A. 2023-02-23 /pmc/articles/PMC9996041/ /pubmed/36911525 http://dx.doi.org/10.3389/fmolb.2023.1106128 Text en Copyright © 2023 Poola, Prabhu, Murthy, Murahari, Krishna, Samantaray and Ramaswamy. 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 | Molecular Biosciences Poola, Anushka A. Prabhu, Prithvi S. Murthy, T. P. Krishna Murahari, Manikanta Krishna, Swati Samantaray, Mahesh Ramaswamy, Amutha Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors |
title | Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors |
title_full | Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors |
title_fullStr | Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors |
title_full_unstemmed | Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors |
title_short | Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors |
title_sort | ligand-based pharmacophore modeling and qsar approach to identify potential dengue protease inhibitors |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996041/ https://www.ncbi.nlm.nih.gov/pubmed/36911525 http://dx.doi.org/10.3389/fmolb.2023.1106128 |
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