دورية أكاديمية
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Deciphering molecular mechanisms underlying the inhibition of β-glucuronidase by xanthones from Centaurium spicatum.

التفاصيل البيبلوغرافية
العنوان: Deciphering molecular mechanisms underlying the inhibition of β-glucuronidase by xanthones from Centaurium spicatum.
المؤلفون: Kamel EM; Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: emad.abdelhameed@science.bsu.edu.eg., Alqhtani HA; Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, Riyadh 11671, Saudi Arabia., Bin-Jumah M; Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, Riyadh 11671, Saudi Arabia., Rudayni HA; Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh 11623, Saudi Arabia., El-Bassuony AA; Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt., Mokhtar Lamsabhi A; Departamento de Química, Módulo 13, Universidad Autónoma de Madrid, Campus de Excelencia UAM-CSIC Cantoblanco, 28049 Madrid, Spain; Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049 Madrid, Spain.
المصدر: Bioorganic chemistry [Bioorg Chem] 2024 Sep; Vol. 150, pp. 107609. Date of Electronic Publication: 2024 Jul 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
مواضيع طبية MeSH: Glucuronidase*/antagonists & inhibitors , Glucuronidase*/metabolism , Xanthones*/chemistry , Xanthones*/pharmacology , Enzyme Inhibitors*/pharmacology , Enzyme Inhibitors*/chemistry , Molecular Docking Simulation*, Dose-Response Relationship, Drug ; Molecular Dynamics Simulation ; Molecular Structure ; Structure-Activity Relationship ; Humans ; Glycoproteins
مستخلص: Herein, we scrutinized the inhibitory potential of five xanthones and a flavonoid, sourced from Centaurium spicatum, against β-glucuronidase activity. The results showed that gentisin and azaleatin emerged as the most potent inhibitors, with significantly lower IC 50 values of 0.96 ± 0.10 and 0.57 ± 0.04 μM, respectively. The evaluation of enzyme kinetics unveiled that the isolated xanthones manifested inhibition of β-glucuronidase through a mixed inhibition mode, whereas azaleatin exhibited a noncompetitive inhibition mechanism. The findings from molecular docking analysis unveiled that the compounds under investigation, particularly azaleatin, displayed comparatively diminished binding affinities towards β-glucuronidase. Furthermore, the tested drugs were shown to occupy a common binding site as the employed reference drug. Our comprehensive Molecular Dynamics (MD) simulations analysis revealed consistent trajectories for the investigated drugs, wherein azaleatin and gentisin demonstrated notable stabilization of energy levels. Analysis of various MD parameters revealed that drugs with the lowest IC 50 values maintained relatively stable interactions with β-glucuronidase. These drugs were shown to exert notable alterations in their conformation or flexibility upon complexation with the target enzyme. Conversely, the flexibility and accessibility of β-glucuronidase was reduced upon drug binding, particularly with azaleatin and gentisin, underscoring the stability of the drug-enzyme complexes. Analysis of Coul-SR and LJ-SR interaction energies unveiled consistent and stable interactions between certain isolated drugs and β-glucuronidase. Azaleatin notably displayed the lowest average Coul-SR interaction energy, suggesting strong electrostatic interactions with the enzyme's active site and significant conformational variability during simulation. Remarkably, LJ-SR interaction energies across different xanthones complexes were more negative than their Coul-SR counterparts, emphasizing the predominant role of van der Waals interactions, encompassing attractive dispersion and repulsive forces, in stabilizing the drug-enzyme complexes rather than electrostatic interactions.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: Enzyme kinetics; Molecular docking; Molecular dynamics simulations; Xanthones; β-glucuronidase
المشرفين على المادة: EC 3.2.1.31 (Glucuronidase)
0 (Xanthones)
0 (Enzyme Inhibitors)
0 (beta-glucuronidase inhibitor)
0 (Glycoproteins)
تواريخ الأحداث: Date Created: 20240704 Date Completed: 20240719 Latest Revision: 20240722
رمز التحديث: 20240722
DOI: 10.1016/j.bioorg.2024.107609
PMID: 38964145
قاعدة البيانات: MEDLINE
الوصف
تدمد:1090-2120
DOI:10.1016/j.bioorg.2024.107609