Metabolic conditions linked to excessive fructose intake, including obesity, non-alcoholic fatty liver disease (NAFLD), abnormal blood lipid profiles, and type 2 diabetes, represent major worldwide public health concerns. Ketohexokinase C (KHK-C), the primary enzyme responsible for fructose phosphorylation, has emerged as an attractive target for therapeutic intervention. α-Mangostin, a prenylated xanthone derived from natural sources, has shown potent inhibitory activity against KHK-C, motivating the search for structural analogs with greater potency. The objective of this investigation was to discover α-Mangostin derivatives exhibiting stronger inhibition of KHK-C for potential use in managing these metabolic diseases. A collection of 1,383 structural analogs was assembled from publicly available chemical repositories and published studies. Candidates were evaluated through a multi-step computational pipeline involving molecular docking simulations, estimation of binding free energies, prediction of pharmacokinetic profiles, molecular dynamics trajectories, and quantum mechanical calculations. The binding affinity of α-Mangostin (−37.34 kcal/mol) was used as the reference standard. Sixteen compounds displayed binding affinities exceeding those of α-Mangostin (ranging from −45.51 to −61.3 kcal/mol), the synthetic inhibitor LY-3522348 (−45.36 kcal/mol), and previously described inhibitors obtained from marine organisms (−22.74 to −51.83 kcal/mol). Five lead compounds (designated as hits 7, 8, 9, 13, and 15) not only achieved higher binding affinities but also demonstrated more favorable drug-like and pharmacokinetic characteristics than α-Mangostin, LY-3522348, and the marine-derived compounds, suggesting improved prospects for in vivo efficacy. Of these, hit 8 stood out with the strongest binding free energy (−61.30 kcal/mol), complete predicted oral bioavailability, greater resistance to metabolic degradation, and consistent stability throughout molecular dynamics simulations. Hit 8 was identified as the top candidate owing to its exceptional binding strength, advantageous pharmacokinetic behavior, and reliable target engagement with KHK-C. These results underscore its therapeutic promise for fructose-associated metabolic syndromes and support the need for subsequent preclinical and clinical studies.
