Targeting the Keap1-Nrf2 pathway: Computational prediction of date palm polyphenols as potential antioxidant activators with drug-likeness and ADME-Tox evaluation

Abstract

The date palm fruit polyphenols confer substantial antioxidant and cytoprotective activity. Elucidating their molecular basis is critical to unlocking their therapeutic potential in oxidative stress-associated pathologies. Polyphenolic constituents identified in two Moroccan cultivars were subjected to a multi-layered computational investigation. Electronic structure characterization was conducted via density functional theory (DFT) at the B3LYP/6-31G(d,p) level, yielding reactivity descriptors including HOMO-LUMO energies and molecular electrostatic potential profiles. Binding affinity toward the Kelch domain of Keap1 (PDB: 4L7B) was evaluated through molecular docking. Pharmaceutical viability was assessed by screening all eleven polyphenols against drug-likeness criteria alongside ADME and toxicological parameters. The computational evidence supports a dual mechanistic framework for the antioxidant activity of date polyphenols, encompassing both direct free radical neutralization and transcriptional activation of the Keap1-Nrf2 cytoprotective pathway. Ellagic acid exhibited the most favorable Keap1 binding profile (−10.0 kcal/mol), followed by catechin and epicatechin. The stability of the top-ranked ellagic acid–Keap1 complex was further confirmed by molecular dynamics (MD) simulations and MM-GBSA/MM-PBSA binding free energy analysis, demonstrating its strong binding affinity and stable interaction with the target protein. Ten of eleven compounds fulfilled drug-likeness requirements, and select phenolic acids, notably ferulic acid and p-hydroxyphenylacetic acid, demonstrated predicted blood-brain barrier permeability, underscoring potential applications in neurodegenerative disease. All compounds displayed acceptable safety margins across mutagenicity and hepatotoxicity endpoints. Collectively, these findings computationally suggest ellagic acid, catechin, and epicatechin as high-priority candidates warranting empirical validation as potential natural Keap1 inhibitors.