Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles
Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. β-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human β-try...
| Główni autorzy: | , , , , |
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| Format: | Artykuł |
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Taylor and Francis Group
2023
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| _version_ | 1825939799773544448 |
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| author | Yu, Chai Xin Tan, Jian Wei Rullah, Kamal Imran, Syahrul Tham, Chau Ling |
| author_facet | Yu, Chai Xin Tan, Jian Wei Rullah, Kamal Imran, Syahrul Tham, Chau Ling |
| author_sort | Yu, Chai Xin |
| collection | UPM |
| description | Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. β-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human β-tryptase inhibitors through computational studies. Thirty-four α-keto-[1,2,3]-oxadiazoles scaffold-based compounds were used to generate 2D-QSAR models and for molecular docking studies with β-tryptase (PDB Code 4A6L). In addition, molecular dynamics (MD) simulation and molecular mechanics generalised born surface area (MM-GBSA) analysis on the binding of the reported most active compound, compound 11e, towards β-tryptase were performed. Finally, a structure-based pharmacophore model was generated. The selected 2D-QSAR models have statistically proven good models by internal and external validation as well as the y-randomization test. The docking results of compound 11e showed lower CDOCKER energy than the 4A6L co-crystallised ligand and a similar binding pattern as the 4A6L co-crystallised ligand. From molecular dynamics simulation, 4A6L in compound 11e bound state has RMSD below 2 Å throughout the 500 ns simulation, indicating the docked complex is stable. Besides, MM-GBSA analysis suggested the 4A6L-compound 11e docked complex (−66.04 Kcal/mol) is structurally as stable as the 4A6L-native ligand co-crystallized structure (−66.84 Kcal/mol). The best pharmacophore model identified features included hydrogen bond acceptor, ionic interaction, hydrophobic interaction, and aromatic ring, which contribute to the inhibitory potency of a compound. This study supplied insight and knowledge for developing novel chemical compounds with improved inhibition of β-tryptase. Communicated by Ramaswamy H. Sarma. |
| first_indexed | 2024-09-25T03:42:17Z |
| format | Article |
| id | upm.eprints-110028 |
| institution | Universiti Putra Malaysia |
| last_indexed | 2024-09-25T03:42:17Z |
| publishDate | 2023 |
| publisher | Taylor and Francis Group |
| record_format | dspace |
| spelling | upm.eprints-1100282024-07-16T07:53:08Z http://psasir.upm.edu.my/id/eprint/110028/ Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles Yu, Chai Xin Tan, Jian Wei Rullah, Kamal Imran, Syahrul Tham, Chau Ling Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. β-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human β-tryptase inhibitors through computational studies. Thirty-four α-keto-[1,2,3]-oxadiazoles scaffold-based compounds were used to generate 2D-QSAR models and for molecular docking studies with β-tryptase (PDB Code 4A6L). In addition, molecular dynamics (MD) simulation and molecular mechanics generalised born surface area (MM-GBSA) analysis on the binding of the reported most active compound, compound 11e, towards β-tryptase were performed. Finally, a structure-based pharmacophore model was generated. The selected 2D-QSAR models have statistically proven good models by internal and external validation as well as the y-randomization test. The docking results of compound 11e showed lower CDOCKER energy than the 4A6L co-crystallised ligand and a similar binding pattern as the 4A6L co-crystallised ligand. From molecular dynamics simulation, 4A6L in compound 11e bound state has RMSD below 2 Å throughout the 500 ns simulation, indicating the docked complex is stable. Besides, MM-GBSA analysis suggested the 4A6L-compound 11e docked complex (−66.04 Kcal/mol) is structurally as stable as the 4A6L-native ligand co-crystallized structure (−66.84 Kcal/mol). The best pharmacophore model identified features included hydrogen bond acceptor, ionic interaction, hydrophobic interaction, and aromatic ring, which contribute to the inhibitory potency of a compound. This study supplied insight and knowledge for developing novel chemical compounds with improved inhibition of β-tryptase. Communicated by Ramaswamy H. Sarma. Taylor and Francis Group 2023-01-29 Article PeerReviewed Yu, Chai Xin and Tan, Jian Wei and Rullah, Kamal and Imran, Syahrul and Tham, Chau Ling (2023) Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles. Journal of Biomolecular Structure and Dynamics, 41 (22). pp. 12978-12996. ISSN 0739-1102; ESSN: 1538-0254 https://www.tandfonline.com/doi/full/10.1080/07391102.2023.2171131 10.1080/07391102.2023.2171131 |
| spellingShingle | Yu, Chai Xin Tan, Jian Wei Rullah, Kamal Imran, Syahrul Tham, Chau Ling Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles |
| title | Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles |
| title_full | Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles |
| title_fullStr | Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles |
| title_full_unstemmed | Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles |
| title_short | Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles |
| title_sort | insight parameter drug design for human β tryptase inhibition integrated molecular docking qsar molecular dynamics simulation and pharmacophore modelling studies of α keto 1 2 4 oxadiazoles |
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