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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1106128/full |
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| author | Anushka A. Poola Prithvi S. Prabhu T. P. Krishna Murthy Manikanta Murahari Swati Krishna Mahesh Samantaray Amutha Ramaswamy |
| author_facet | Anushka A. Poola Prithvi S. Prabhu T. P. Krishna Murthy Manikanta Murahari Swati Krishna Mahesh Samantaray Amutha Ramaswamy |
| author_sort | Anushka A. Poola |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T07:37:43Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-10T07:37:43Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-44a8ca789e0c4dd5920428974f6e32bb2023-02-23T12:25:27ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-02-011010.3389/fmolb.2023.11061281106128Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitorsAnushka A. Poola0Prithvi S. Prabhu1T. P. Krishna Murthy2Manikanta Murahari3Swati Krishna4Mahesh Samantaray5Amutha Ramaswamy6Department of Biotechnology, M. S. Ramaiah Institute of Technology, Bengaluru, Karnataka, IndiaDepartment of Biotechnology, M. S. Ramaiah Institute of Technology, Bengaluru, Karnataka, IndiaDepartment of Biotechnology, M. S. Ramaiah Institute of Technology, Bengaluru, Karnataka, IndiaDepartment of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh, IndiaDepartment of Biotechnology, M. S. Ramaiah Institute of Technology, Bengaluru, Karnataka, IndiaDepartment of Bioinformatics, Pondicherry University, Pondicherry, IndiaDepartment of Bioinformatics, Pondicherry University, Pondicherry, IndiaThe 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.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1106128/fullDengueQSARpharmacophore modelingdockingmolecular dynamics |
| spellingShingle | Anushka A. Poola Prithvi S. Prabhu T. P. Krishna Murthy Manikanta Murahari Swati Krishna Mahesh Samantaray Amutha Ramaswamy Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors Frontiers in Molecular Biosciences Dengue QSAR pharmacophore modeling docking molecular dynamics |
| 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 | Dengue QSAR pharmacophore modeling docking molecular dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1106128/full |
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