تجاوز إلى المحتوى الرئيسي

Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach

Author name : MAGDI AWADALLA MOHAMED ELHUSSEIN
Publication Date : 2025-03-06
Journal Name : Pharmaceuticals

Abstract

Abstract: Background/Objectives: Fructose-driven metabolic disorders, such as obesity,
non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant
global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism,
is a promising therapeutic target. α-Mangostin, a naturally occurring prenylated xanthone,
has been identified as an effective KHK-C inhibitor, prompting exploration of its analogs
for enhanced efficacy. This study aimed to identify α-Mangostin analogs with improved
inhibitory properties against KHK-C to address these disorders. Methods: A library of
1383 analogs was compiled from chemical databases and the literature. Molecular docking, binding free energy calculations, pharmacokinetic assessments, molecular dynamics
simulations, and quantum mechani–cal analyses were used to screen and evaluate the
compounds. α-Mangostin’s binding affinity (37.34 kcal/mol) served as the benchmark.
Results: Sixteen analogs demonstrated binding affinities superior to α-Mangostin (from
−45.51 to −61.3 kcal/mol), LY-3522348 (−45.36 kcal/mol), and reported marine-derived inhibitors (from −22.74 to −51.83 kcal/mol). Hits 7, 8, 9, 13, and 15 not only surpassed these
benchmarks in binding affinity, but also exhibited superior pharmacokinetic properties
compared to α-Mangostin, LY-3522348, and marine-derived inhibitors, indicating strong
in vivo potential. Among these, hit 8 emerged as the best performer, achieving a binding
free energy of −61.30 kcal/mol, 100% predicted oral absorption, enhanced metabolic stability, and stable molecular dynamics. Conclusions: Hit 8 emerged as the most promising
candidate due to its superior binding affinity, favorable pharmacokinetics, and stable interactions with KHK-C. These findings highlight its potential for treating fructose-driven
metabolic disorders, warranting further experimental validation.

Keywords

xanthones; fructose; ketohexokinase C; obesity; diabetes; dyslipidemia

Publication Link

https://www.mdpi.com/1424-8247/18/1/126

Block_researches_list_suggestions

Suggestions to read

HIDS-IoMT: A Deep Learning-Based Intelligent Intrusion Detection System for the Internet of Medical Things
Ahlem . Harchy Ep Berguiga
Generalized first approximation Matsumoto metric
AMR SOLIMAN MAHMOUD HASSAN
Structure–Performance Relationship of Novel Azo-Salicylaldehyde Disperse Dyes: Dyeing Optimization and Theoretical Insights
EBTSAM KHALEFAH H ALENEZY
“Synthesis and Characterization of SnO₂/α-Fe₂O₃, In₂O₃/α-Fe₂O₃, and ZnO/α-Fe₂O₃ Thin Films: Photocatalytic and Antibacterial Applications”
Asma Arfaoui
تواصل معنا