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 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. ISSN 0739-1102 E-ISSN 1538-0254

Preview	PDF (WOS) - Supplemental Material Download (278kB) | Preview
Preview	PDF (SCOPUS) - Supplemental Material Download (113kB) | Preview
	PDF (Article) - Published Version Restricted to Repository staff only Download (4MB) | Request a copy

Abstract

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.

Item Type:	Article (Journal)
Uncontrolled Keywords:	b-tryptase inhibitors; QSAR; docking; molecular dynamics; pharmacophore
Subjects:	R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Pharmacy Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry
Depositing User:	Dr Kamal Rullah
Date Deposited:	21 Mar 2023 08:20
Last Modified:	21 Mar 2023 08:28
URI:	http://irep.iium.edu.my/id/eprint/104156

Actions (login required)

View Item