Evaluation of N-palmitoylethanolamine (PEA) binding to nuclear receptors through docking and molecular dynamics studies

Abstract

N-palmitoylethanolamine (PEA) is an endogenous bioactive compound recognized for its anti-inflammatory effects and its role in tissue protection and repair. Despite the proposal of peroxisome proliferator-activated receptor alpha (PPARα) as a potential receptor for PEA, direct evidence of binding remains insufficient. This study offers a comprehensive analysis of human nuclear receptors (NRs) through structural bioinformatics and molecular docking, evaluating a total of 367 unique NR structures across 47 subfamilies.

To explore the stability and binding affinity of PEA with selected nuclear receptors, we conducted molecular dynamics simulations following initial docking assessments. The results revealed Hepatocyte Nuclear Factor 4-alpha (HNF4α) as the highest-ranking receptor with a global score of 0.884, closely followed by Hepatocyte Nuclear Factor 4-gamma (HNF4γ) at 0.871 and Retinoic Acid Receptor gamma-1 (RARγ-1) at 0.829. Among these, HNF4γ demonstrated the strongest affinity for PEA, supported by consistent simulation results. In contrast, the PPARα receptor ranked 44th with a global score of 0.519, indicating that PEA may engage more effectively with other nuclear receptors.

In conclusion, this study underscores PEA's potential as a multi-target therapeutic agent through its interactions with various nuclear receptors, particularly HNF4γ and the Mineralocorticoid Receptor (MR). The ability of PEA to influence multiple signaling pathways suggests its promise in addressing complex diseases associated with inflammation and metabolic disorders. Additionally, the integration of Root Mean Square Deviation (RMSD) and Gibbs free energy (ΔG) analyses further elucidates the stability and binding affinities of PEA, providing a foundation for future research into its therapeutic applications.