Molecular docking analysis and dynamics simulation of ethanol extract of Citrus sinensis as a Keap1 and NMDA inhibitor in brain injury

Abstract

Traumatic brain injury is a significant cause of mortality in young adults and disability in all age groups. This is followed by secondary injury involving various processes, such as oxidative stress which induce neuronal apoptosis. The present study aimed to analyze the active compounds of <em>Citrus sinensis</em> and predict its antioxidative activity in traumatic brain injury. Liquid chromatography/high resolution mass spectrometry (LC/HRMS) was used to identify compounds in the ethanol extract of <em>Citrus sinensis</em> peel. We analyzed pharmacokinetics, blood‑brain barrier (BBB) permeability and the toxicity of active compounds in <em>Citrus sinensis</em> peel using SwissADME and OSIRIS. The compounds with a good BBB permeability were subjected to molecular docking analysis to identify the molecular interaction with Kelch‑like ECH associated protein 1 (Keap1) and N‑methyl‑D‑aspartate (NMDA) proteins using PyRx, PyMol and Discovery Studio software. The results of the LC/HRMS analysis revealed 16 active compounds contained in the ethanol extract of the orange peel. Nootkatone, alminoprofen, linoleic acid, chanoclavine, scoparone and tangeretin were predicted to pass the BBB. The active compounds of <em>Citrus sinensis</em> strongly bound against Keap1 and NMDA, particularly scoparone and nootkatone. The strong binding affinity of scoparone‑Keap1 was ‑5.0, more than that of the control ligand, and that of nootkatone‑NMDA was ‑7.8, similar to the control ligand. The active compounds of <em>Citrus sinensis</em> peel exhibited inhibitory potential, good pharmacokinetics and toxicity profiles against Keap1 and NMDA. On the whole, these findings suggest that ethanol extract of Citrus sinensis peel has potential for use as an oxidative stress inhibitor in the treatment of brain injury.