Composition analysis, QSAR, molecular docking, molecular dynamics simulation and ADMET profiles of Citrus aurantium fruit essential oil compounds as inhibitors of NF-κB and MAPK in brain injury.

Brain injury represents a major global health challenge, marked by complex pathophysiological mechanisms involving secondary neuroinflammation driven by NF-κB and MAPK pathway activation. Despite its clinical significance, no effective therapies currently exist for brain injury management. Essential oils (EOs) have arisen as potential therapeutic agents owing to their bioactive components demonstrating anti-inflammatory and neuroprotective effects. This study identified and characterized bioactive compounds and the inhibitory potential of Citrus aurantium fruit essential oil (CAFEO) compounds against NF-κB and p38 MAPK using an integrated computational approach. CAFEO was extracted by hydrodistillation, and GC-MS analysis identified 64 bioactive constituents. QSAR modeling predicted biological activity with high correlation coefficients (R^2 > 0.6, Q^2 > 0.7) and 19 CAFEO compounds showed comparable or higher predicted activity against NF-κB and p38 MAPK compared to standard inhibitors. Molecular docking revealed γ-terpinene (-3.65 kcal/mol) and α-terpineol (-3.81 kcal/mol) as the most potent binders, interacting with critical amino acids residues of NF-κB and p38 MAPK. Molecular dynamics simulations further demonstrated their stable binding conformations over 300 ns. Pharmacokinetic profiling (SwissADME) confirmed favorable drug-like properties, including blood-brain barrier permeability, while ProTox-II predictions indicated low toxicity. These findings suggest CAFEO, particularly γ-terpinene and α-terpineol as a natural source of NF-κB/p38 MAPK inhibitors with potential to mitigate brain injury-induced inflammation, offering a foundation for future preclinical investigations into CAFEO-derived therapeutics.