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

被引:2
作者
Yu, Chai Xin [1 ]
Tan, Jian Wei [1 ]
Rullah, Kamal [2 ]
Imran, Syahrul [3 ,4 ]
Tham, Chau Ling [1 ]
机构
[1] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Biomed Sci, Serdang, Selangor, Malaysia
[2] Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kulliyyah Pharm, Drug Discovery & Synthet Chem Res Grp, Kuantan, Pahang, Malaysia
[3] Univ Teknol MARA, Atta Ur Rahman Inst Nat Prod Discovery AuRIns, Cawangan Selangor, Kampus Puncak Alam, Puncak Alam, Selangor, Malaysia
[4] Univ Teknol MARA UiTM, Fac Appl Sci, Shah Alam, Selangor, Malaysia
关键词
beta-tryptase inhibitors; QSAR; docking; molecular dynamics; pharmacophore; MAST-CELL TRYPTASE; EDGE ADJACENCY RELATIONSHIPS; POTENT; DISCOVERY; DENGUE; TETRAMER; SAR; IDENTIFICATION; REQUIREMENTS; DERIVATIVES;
D O I
10.1080/07391102.2023.2171131
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. beta-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 beta-tryptase inhibitors through computational studies. Thirty-four alpha-keto-[1,2,3]-oxadiazoles scaffold based compounds were used to generate 2D-QSAR models and for molecular docking studies with beta-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 beta-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 angstrom 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 beta-tryptase.
引用
收藏
页码:12978 / 12996
页数:19
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