Natural compounds as PPAR-γ modulators in inflammatory bowel disease: Insights from molecular docking and dynamics simulations

Inflammatory bowel disease (IBD) comprises a group of chronic, relapsing disorders of the gastrointestinal tract associated with significant morbidity. Current therapies, including anti-inflammatory agents and immunosuppressants, are often limited by adverse effects and inadequate efficacy, underscoring the need for novel treatment. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a critical role in regulating inflammation and maintaining intestinal homeostasis, making it a promising therapeutic target for IBD management. Despite its potential, the molecular interactions between natural compounds and PPAR-γ remain inadequately characterized. The present study employed computational approaches to identify and evaluate natural compounds as potential PPAR-γ modulators for IBD management. Fifty phytochemicals, relevant to PPAR-γ modulation, were retrieved from the PubChem database and assessed for their binding affinity to PPAR-γ using molecular docking analyses. Their physicochemical, pharmacokinetics, and drug-likeness properties were evaluated using SwissADME, while toxicity predictions were performed via the ProTox 3.0 web server. Based on docking scores and ADMET profiles, five top-ranking compounds were further subjected to 100 ns molecular dynamics (MD) simulations and MM-GBSA binding free energy calculations to assess their binding stability and energetics. From amongst the assessed phytochemicals, oroxyloside exhibited the highest docking score (−10.0 kcal/mol). Sargahydroquinoic acid and sargaquinoic acid also demonstrated favorable stability and interaction profiles, whereas berberine and amorfrutin B showed moderate but consistent binding behaviour. The MD simulations confirmed strong and stable binding interactions for sargahydroquinoic acid and sargaquinoic acid. The findings of current studies highlight the potential of sargahydroquinoic acid and sargaquinoic acid as natural PPAR-γ modulators and as promising candidates for the development of novel IBD therapies. Overall, the study identified these natural compounds as promising PPAR-γ modulators for the treatment of IBD.