Exploring Marine-Derived Compounds: In Silico Discovery of Selective Ketohexokinase (KHK) Inhibitors for Metabolic Disease Therapy.

The increasing prevalence of metabolic diseases, including nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes, poses significant global health challenges. Ketohexokinase (KHK), an enzyme crucial in fructose metabolism, is a potential therapeutic target due to its role in these conditions. This study focused on the discovery of selective KHK inhibitors using in silico methods. We employed structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches, beginning with molecular docking to identify promising compounds, followed by induced-fit docking (IFD), molecular mechanics generalized Born and surface area continuum solvation (MM-GBSA), and molecular dynamics (MD) simulations to validate binding affinities. Additionally, shape-based screening was conducted to assess structural similarities. The findings highlight several potential inhibitors with favorable ADMET profiles, offering promising candidates for further development in the treatment of fructose-related metabolic disorders.