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

• Main Authors: Yu, Chai Xin, Tan, Jian Wei, Rullah, Kamal, Imran, Syahrul, Tham, Chau Ling
• Format: Article
• Language: English; English; English
• Published: Taylor and Francis 2023
• Subjects: RS403 Materia Medica-Pharmaceutical Chemistry
• Online Access: http://irep.iium.edu.my/104156/4/104156_Insight%20parameter%20drug%20design%20for%20human%20%CE%B2-tryptase_WOS.pdf; http://irep.iium.edu.my/104156/5/104156_Insight%20parameter%20drug%20design%20for%20human%20%CE%B2-tryptase_SCOPUS.pdf; http://irep.iium.edu.my/104156/6/104156_Insight%20parameter%20drug%20design%20for%20human%20%CE%B2-tryptase.pdf; http://irep.iium.edu.my/104156/; https://www.tandfonline.com/doi/abs/10.1080/07391102.2023.2171131?journalCode=tbsd20; https://doi.org/10.1080/07391102.2023.2171131
• Institution: Universiti Islam Antarabangsa Malaysia

Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. b-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 b-tryptase inhibitors through computational studies. Thirty-four a-keto-[1,2,3]-oxadiazoles scaffoldbased compounds were used to generate 2D-QSAR models and for molecular docking studies with b-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 b-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 b-tryptase.