Theoretical insights into the binding of mono/di-ethyl phthalates to superoxide dismutase and associated structural changes impairing antioxidant activity: A coupled molecular docking and dynamics simulation approach.

Phthalic acid esters (PAEs) are plasticizers known to increase oxidative stress by impairing antioxidant defenses, including superoxide dismutase (SOD) activity. Since oxidative stress plays a critical role in disease development, the disruption of SOD function by PAEs presents a significant concern. However, the precise molecular mechanisms underlying the regulation of SOD activity remain unclear. This study investigated how diethyl phthalate (DEP) and its major metabolite, monoethyl phthalate (MEP), affected SOD activity using molecular docking and dynamics simulations. The results revealed that both DEP and MEP bound to SOD through weak hydrophilic interactions and hydrogen bonds with residues Lys9, Thr17, Asn51, Thr52, and Arg141 in the bottom of the enzyme's two subunit cavities. These interactions triggered structural changes, particularly in the electrostatic loop and catalytic channels, destabilizing SOD. DEP and MEP increased the enzyme's radius of gyration and solvent-accessible surface area while disrupting intra-protein interactions. MEP showed a stronger inhibitory effect, significantly altering SOD's conformation. This change correlated with reduced catalytic activity (R > 0.9). Consequently, the inhibition of the enzyme is primarily due to the disruption of Arg141's conformation and function, which weakens SOD's antioxidant defense and potentially contributes to diseases related to oxidative damage. These results underscore the health risks posed by PAEs, especially following metabolic transformation, and highlight the importance of addressing their oxidative impact.