Molecular docking analysis of interactions between flavonoids and the Neh1 Domain of NRF2

Abstract

Background: Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in regulating cellular responses to oxidative stress and xenobiotic exposure. However, excessive NRF2 activation can enhance cancer cell survival and contribute to chemoresistance. Therefore, increasing attention has been directed toward naturally occurring flavonoids that may modulate NRF2 activity. Molecular docking provides a computational approach for predicting potential interactions between flavonoids and NRF2 and may help identify candidate compounds for further investigation in cancer therapy. Objective: To evaluate the potential interactions of five naturally occurring flavonoids—daidzin, rutin, luteolin, apigenin, and quercetin—with the Neh1 domain of NRF2 using molecular docking and to identify promising candidates for further investigation based on docking scores and ligand efÏciency. Materials and Methods: The potential interactions of five natural flavonoids, namely daidzin, rutin, luteolin, apigenin, and quercetin, with the target region of NRF2 were investigated using molecular docking. Three-dimensional structures of the flavonoids were retrieved from the PubChem database, while the NRF2 protein structure was obtained from the Protein Data Bank (PDB). Molecular docking calculations were performed using the CB-Dock2 web platform, which incorporates the AutoDock Vina algorithm. Results: The docking scores of the selected flavonoids ranged from −64.9 to −77.2. Daidzin exhibited the most favorable docking score (−77.2), followed by apigenin (−72.0) and luteolin (−71.4), whereas rutin showed the least favorable score (−64.9). The calculated RMSD values ranged from 14.766 to 15.344 Å, with relatively small differences among the ligands. Daidzin and apigenin exhibited comparatively lower RMSD values. The reported pose-clustering analysis indicated that all ligands occupied similar binding regions. In terms of ligand efÏciency, apigenin (−2.40), luteolin (−2.30), and quercetin (−2.20) showed comparatively favorable values. Although daidzin had the most favorable docking score, its ligand efÏciency relative to molecular size was comparatively lower. Conclusion: The results suggest that daidzin and apigenin may be candidate compounds for further investigation of potential interactions with the Neh1 domain of NRF2. However, these findings are based solely on computational analysis. Further molecular dynamics simulations and experimental studies are required to validate the predicted interactions and determine their actual effects on NRF2 activity.