Evaluation of Taraxacum officinale phytoconstituents as potential JNK1 inhibitors: Perspectives from ADMET, molecular docking, molecular dynamics, and density functional theory

IF 3.8 Q2 CHEMISTRY, PHYSICAL Chemical Physics Impact Pub Date : 2024-10-22 DOI:10.1016/j.chphi.2024.100757
Sphelele C. Sosibo , Hendrik G. Kruger , Wonder P. Nxumalo , Zimbili Zondi
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Abstract

The impact of activated c-Jun N-terminal kinase isoform JNK1 chemical pathways in insulin biosynthesis poses a potential health risk of glucose intolerance. Blocking the activity of JNK1 is a promising route for the design of anti-diabetic drugs and associated metabolic syndromes. In this study, 17 extracts of Taraxacum officinale were chosen to bind JNK1 and ascertain their modulatory activity. We employed molecular dynamics, density functional theory and three docking approaches: standard precision, extra precision and quantum polarized ligand docking. The best binding free energy results were obtained from the quantum polarized ligand docking, with myricetin (1) showing a docking score of -10.464 kcal/mol, while quercetin (2) and daphnetin (3) displayed values of -9.769 and -7.136 kcal/mol respectively. Following this, 100 ns molecular dynamics simulations with Desmond showed stabilization average root mean square deviations of 2.34, 2.87, and 2.88 Å for myricetin, quercetin and daphnetin. Further, molecular dynamics revealed complexes of myricetin (ΔG = -38.81 kcal/mol) and quercetin (ΔG = -34.99 kcal/mol) as the most stable inside the JNK1 interface. The energy gaps for myricetin, quercetin and daphnetin were estimated to be 6.17, 6.00 and 6.53 eV employing the M06–2X functional in PCM solvation. Further, myricetin showed the strongest intramolecular hydrogen bonding with -13.06 kcal/mol. This study provides insights into possible anti-type-2 diabetes properties of Taraxacum officinale targeting JNK1.

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评估作为潜在 JNK1 抑制剂的蒲公英植物成分:ADMET、分子对接、分子动力学和密度泛函理论的观点
活化的 c-Jun N-terminal 激酶异构体 JNK1 化学途径对胰岛素生物合成的影响构成了葡萄糖不耐受的潜在健康风险。阻断 JNK1 的活性是设计抗糖尿病药物和相关代谢综合征的一条可行途径。本研究选择了 17 种蒲公英提取物与 JNK1 结合并确定其调节活性。我们采用了分子动力学、密度泛函理论和三种对接方法:标准精度对接、额外精度对接和量子极化配体对接。量子极化配体对接获得了最佳的结合自由能结果,其中杨梅素(1)的对接得分为-10.464 kcal/mol,而槲皮素(2)和水黄皮素(3)的对接得分分别为-9.769和-7.136 kcal/mol。随后,使用 Desmond 进行的 100 ns 分子动力学模拟显示,杨梅素、槲皮素和萘素的稳定化平均均方根偏差分别为 2.34、2.87 和 2.88 Å。此外,分子动力学显示,在 JNK1 界面内,三叶草素(ΔG = -38.81 kcal/mol)和槲皮素(ΔG = -34.99 kcal/mol)的复合物最为稳定。利用 PCM 溶胶中的 M06-2X 函数,估计出杨梅素、槲皮素和萘皮素的能隙分别为 6.17、6.00 和 6.53 eV。此外,杨梅素的分子内氢键最强,为 -13.06 kcal/mol。这项研究有助于深入了解蒲公英以 JNK1 为靶点可能具有的抗 2 型糖尿病特性。
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来源期刊
Chemical Physics Impact
Chemical Physics Impact Materials Science-Materials Science (miscellaneous)
CiteScore
2.60
自引率
0.00%
发文量
65
审稿时长
46 days
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