Comprehensive modeling of the antioxidant mechanism of ebselen

Three possible catalytic cycles for ebselen have been comprehensively modeled by theoretical calculations using density functional theory (DFT) at a mixed basis set level; the 6-31G(d) basis set for hydrocarbon fragments and the 6-31++G(d,p) basis set for other atoms. The 2→3→3′→3′′→4′→4→2 cycle is the main pathway in the glutathione peroxidase (GPx) cycle (cycle A), and IM3→TS3 is the rate controlling process. The 1→5→8→8′′→1 cycle is the main pathway for the oxidation cycle (cycle B), and the rate controlling step is the 8′′→1 step. Ebselen reacts with the selenol 3 to form the diselenide 9, and this is the rate controlling step for cycle C. The extremely high energy barrier for the IM9→TS9 process indicates that cycle C is unlikely to occur in vivo. Although cycle B is favored based on the energy analysis, with a maximum energy barrier of only 26.68kcal/mol at the mixed basis set level, it is generally unlikely to have very high concentrations of peroxides present in vivo. The results indicate that in order to improve the antioxidant activity of ebselen, it would be necessary to suitably modify the molecular structure of ebselen to reduce the energy barrier of the IM3→TS3 process.