Environmental toxicants like dibutyl phthalate (DBP) trigger oxidative stress by increasing reactive oxygen species (ROS), disrupting cellular redox balance and contributing to chronic diseases. Flavonoids are known antioxidants, but their molecular interactions with key antioxidant enzymes are not fully understood. This study used molecular docking to examine the binding of morin, myricetin, and quercetin to four major antioxidant targets: Nrf2-Keap1, superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR), with epigallocatechin gallate (EGCG) as a reference Nrf2 activator. Docking results revealed that EGCG consistently exhibited the strongest binding affinity across all enzymes, while quercetin and morin demonstrated comparable or superior interactions in specific cases, particularly with CAT and GR. Key residues such as Ala556 in Nrf2-Keap1, Arg203 in CAT, and Lys66 in GR were consistently involved in ligand stabilization through hydrogen bonding, π–π stacking, and hydrophobic contacts. ADMET predictions indicated that morin and quercetin possess favorable pharmacokinetic and drug-likeness properties, including good gastrointestinal absorption and minimal structural alerts. In contrast, EGCG displayed limited absorption and bioavailability despite its high binding affinity. These findings underscore the therapeutic potential of selected flavonoids in oxidative stress-related disorders and support their further exploration as modulators of endogenous antioxidant defense mechanisms

Flavonoids, Molecular docking, Nrf2-Keap1, Antioxidant enzymes, Catalase, Glutathione reductase, Superoxide dismutase, EGCG, ADMET, Oxidative stress modulation

This study provides a detailed comparative analysis of the molecular interactions between selected flavonoids and key antioxidant enzymes involved in cellular redox homeostasis. Docking results identified morin, myricetin, and quercetin as effective ligands with moderate to strong binding affinities toward Nrf2-Keap1, CAT, GR, and SOD, comparable to or approaching the performance of the reference antioxidant EGCG. Key active-site residues, including Ala556 (Nrf2), Arg203 (CAT), Lys66 (GR), and Glu21/Lys23 (SOD), were critical for ligand anchoring and stabilization. ADMET evaluations revealed that morin and quercetin possess better oral bioavailability and fewer pharmacological liabilities than EGCG, suggesting a more favorable profile for therapeutic development. Refining the understanding of these interactions not only underscores the mechanistic role of flavonoids in mitigating oxidative stress but also addresses the broader issue of countering cellular damage caused by environmental endocrine disruptors. This highlights the therapeutic relevance of targeting the Keap1-Nrf2-ARE axis and related antioxidant enzymes in oxidative stress-linked reproductive dysfunctions. Further in vitro and in vivo validation studies are warranted to confirm the bioactivity of these flavonoids under physiological conditions. Additionally, structural modifications or nanoformulation approaches could be explored to enhance the bioavailability and tissue-targeting efficiency of these compounds. Long-term studies may also investigate their potential as preventive agents or adjuvants in the treatment of oxidative stress-induced diseases, particularly in reproductive toxicology and chronic inflammatory disorders

Y. Jhansi Lakshmi, B. Umadevi, K. Kranthi Kumar and Y. Suneetha (2025). Comparative Docking and Pharmacokinetic Insights into Flavonoid Modulation of Antioxidant Enzymes: A Molecular Basis for Nrf2 Activation and Oxidative Stress Mitigation. Biological Forum, 17(6): 113-121