Antiradical Potency of Diphlorethol: DFT (Density Functional Theory), Molecular Docking, and ADMET Profile

Diphlorethol is a typical phlorotannin with multipharmacological activities. However, its antiradical activity is still ambiguous. The current study aims to evaluate its radical scavenging using thermodynamics and kinetics-based density functional theory (DFT) calculations. The results indicated that the main radical scavenging mechanism in gas and lipid was the formal hydrogen
transfer (FHT), and that for the aqueous medium was the sequential proton loss-electron transfer (SPLET). The kinetic reactions with HOO˙ and CH3OO˙ radicals resulted in the koverall (overall rate constant) of 1.2 × 108–1.6 × 108 M−1 s−1 in water and 3.0 × 100–2.7 × 101 M−1 s−1 in pentyl ethanoate. 4-and 6-OH acted as active centers for radical scavenging. The molecular docking simulation suggested that diphlorethol could serve as a potential inhibitor of the oxidative activity of the Keap1 enzyme, particularly through its interaction with the crucial amino acid residue Arg415. The ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis demonstrated that diphlorethol exhibited favorable pharmacokinetic properties, including good water solubility, high intestinal absorption, and moderate tissue distribution. Diphlorethol did not induce hepatotoxicity or skin sensitization and showed no inhibitory effects on hERG I or hERG II channels, supporting its potential as a safe antioxidant candidate for further development.