Structure-based insights into fatty acid modulation of lipid-sensing nuclear receptors PPARδ/γ for glycemic regulation

This study explores the therapeutic potential of fatty acids (FA1-FA12) in the treatment of diabetes mellitus, focusing on their modulation of lipid-sensing nuclear receptors PPARδ/γ. Network pharmacology analysis highlighted key pathways involved in diabetes, including PI3K-Akt, MAPK, and insulin signaling, with targets such as PPAR, INSR, SLC2A4, and AKT1, suggesting a multi-target approach to disease modulation. To investigate their mechanism of action, a pharmacophore model was developed based on the PPAR-γ inhibitor Pioglitazone, offering insights into the essential structural features for ligand binding. Molecular docking studies revealed that FA1 and FA2 exhibited favorable binding affinities at the active sites of both PPAR-γ and PPAR-δ and MD trajectory analysis to evaluate binding orientation and stability of the molecules and the energy profiles of the molecules FA1 (Palmitic acid) and FA2 (Myristic acid), both in complex with the both PPAR-γ and PPAR-δ protein, were assessed. Additionally, computational analyses, including DFT and ADMET predictions, provided valuable information on the electronic and physicochemical properties of the fatty acids. Although these compounds displayed promising lipophilicity and permeability, their poor aqueous solubility indicates the need for optimization in drug development. Overall, this study lays a foundation for the exploration of fatty acids as potential therapeutic agents for diabetes, particularly through their modulation of PPARδ/γ activity for glycemic regulation. • Network pharmacology reveals FA1-FA12 interact with PI3K-Akt, MAPK, and insulin pathways. • SBDD and docking show FA1 (Palmitic) and FA2 (Myristic) bind strongly to PPAR-γ/δ. • FA1 and FA2 modulate PPAR-γ/δ, enhancing insulin sensitivity and lipid regulation. • Findings suggest potential in lipid metabolism regulation and diabetes management.