Bridging in silico and in vitro perspectives to unravel molecular mechanisms underlying the inhibition of β-glucuronidase by coumarins from Hibiscus trionum

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biophysical chemistry Pub Date : 2024-07-26 DOI:10.1016/j.bpc.2024.107304

Emadeldin M. Kamel , Faris F. Aba Alkhayl , Haifa A. Alqhtani , May Bin-Jumah , Hassan A. Rudayni , Al Mokhtar Lamsabhi

{"title":"Bridging in silico and in vitro perspectives to unravel molecular mechanisms underlying the inhibition of β-glucuronidase by coumarins from Hibiscus trionum","authors":"Emadeldin M. Kamel , Faris F. Aba Alkhayl , Haifa A. Alqhtani , May Bin-Jumah , Hassan A. Rudayni , Al Mokhtar Lamsabhi","doi":"10.1016/j.bpc.2024.107304","DOIUrl":null,"url":null,"abstract":"<div><p>Unraveling the intricacies of β-glucuronidase inhibition is pivotal for developing effective strategies in applications specific to gastrointestinal health and drug metabolism. Our study investigated the efficacy of some <em>Hibiscus trionum</em> phytochemicals as β-glucuronidase inhibitors. The results showed that cleomiscosin A and mansonone H emerged as the most potent inhibitors, with IC<sub>50</sub> values of 3.97 ± 0.35 μM and 10.32 ± 1.85 μM, respectively. Mechanistic analysis of β-glucuronidase inhibition indicated that cleomiscosin A and the reference drug EGCG displayed a mixed inhibition mode against β-glucuronidase, while mansonone H exhibited noncompetitive inhibition against β-glucuronidase. Docking studies revealed that cleomiscosin A and mansonone H exhibited the lowest binding affinities, occupying the same site as EGCG, and engaged significant key residues in their binding mechanisms. Using a 30 ns molecular dynamics (MD) simulation, we explored the interaction dynamics of isolated compounds with β-glucuronidase. Analysis of various MD parameters showed that cleomiscosin A and mansonone H exhibited consistent trajectories and significant energy stabilization with β-glucuronidase. These computational insights complemented experimental findings, underscoring the potential of cleomiscosin A and mansonone H as β-glucuronidase inhibitors.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"313 ","pages":"Article 107304"},"PeriodicalIF":3.3000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biophysical chemistry","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0301462224001339","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Unraveling the intricacies of β-glucuronidase inhibition is pivotal for developing effective strategies in applications specific to gastrointestinal health and drug metabolism. Our study investigated the efficacy of some Hibiscus trionum phytochemicals as β-glucuronidase inhibitors. The results showed that cleomiscosin A and mansonone H emerged as the most potent inhibitors, with IC₅₀ values of 3.97 ± 0.35 μM and 10.32 ± 1.85 μM, respectively. Mechanistic analysis of β-glucuronidase inhibition indicated that cleomiscosin A and the reference drug EGCG displayed a mixed inhibition mode against β-glucuronidase, while mansonone H exhibited noncompetitive inhibition against β-glucuronidase. Docking studies revealed that cleomiscosin A and mansonone H exhibited the lowest binding affinities, occupying the same site as EGCG, and engaged significant key residues in their binding mechanisms. Using a 30 ns molecular dynamics (MD) simulation, we explored the interaction dynamics of isolated compounds with β-glucuronidase. Analysis of various MD parameters showed that cleomiscosin A and mansonone H exhibited consistent trajectories and significant energy stabilization with β-glucuronidase. These computational insights complemented experimental findings, underscoring the potential of cleomiscosin A and mansonone H as β-glucuronidase inhibitors.

Abstract Image

查看原文本刊更多论文

打通硅学和体外研究的视角，揭示芙蓉三香豆素抑制β-葡糖醛酸酶的分子机制

揭示β-葡糖醛酸酶抑制作用的复杂性对于开发胃肠道健康和药物代谢特定应用领域的有效策略至关重要。我们的研究调查了一些芙蓉三叶草植物化学物质作为β-葡糖醛酸酶抑制剂的功效。结果表明，cleomiscosin A 和 mansonone H 是最有效的抑制剂，其 IC50 值分别为 3.97 ± 0.35 μM 和 10.32 ± 1.85 μM。对β-葡萄糖醛酸酶抑制作用的机理分析表明，裂袂木香苷 A 和参考药物 EGCG 对β-葡萄糖醛酸酶具有混合抑制作用，而曼松酮 H 对β-葡萄糖醛酸酶具有非竞争性抑制作用。Docking 研究表明，cleomiscosin A 和 mansonone H 与 EGCG 的结合亲和力最低，占据了相同的位点，并且在其结合机制中参与了重要的关键残基。利用 30 ns 分子动力学（MD）模拟，我们探索了分离化合物与 β-葡萄糖醛酸酶的相互作用动力学。对各种 MD 参数的分析表明，cleomiscosin A 和 mansonone H 与 β-葡萄糖醛酸酶表现出一致的轨迹和显著的能量稳定。这些计算见解与实验结果相辅相成，凸显了裂米苷 A 和曼松酮 H 作为 β-葡萄糖醛酸酶抑制剂的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Biophysical chemistry 生物-生化与分子生物学

CiteScore

6.10

自引率

10.50%

发文量

121

审稿时长

20 days

期刊介绍： Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.