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

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.