Tuning the activity of glutathione peroxidase mimics through intramolecular Se⋯N,O interactions: A DFT study incorporating solvent-assisted proton exchange (SAPE)

Abstract

Diaryl diselenide mimics of the antioxidant selenoprotein glutathione peroxidase (GPx) often incorporate intramolecular Se⋯N,O interactions to enhance their GPx-like activity. Although the strength of the interaction is defined by the Lewis basicity of the donating group and the strength of the Se–X bond, there is not a clear relationship between the interaction and the GPx-like activity. Density-functional theory and natural bond orbital (NBO) calculations are used to show the range of Se⋯N,O interactions for various functional groups. The strongest interactions are found for groups which stabilize the donor–acceptor interaction through aromatic stabilization. The activation barriers for the GPx-like mechanism of activity of several substituted areneselenols are calculated using DFT and solvent-assisted proton exchange (SAPE), a technique that incorporates networks of solvent molecules into the theoretical model to facilitate proton transfer between sites in the reactant and product. DFT-SAPE models show that, in addition to decreasing the barrier to oxidation of the selenol, Se⋯N,O interactions generally increase the barriers for selenenic acid reduction and selenol regeneration because the Se⋯N,O interaction must be broken for the reaction to proceed. Calculated activation barriers for the rate-determining step are consistent with the relative experimental GPx-like activities of a series of diaryl diselenides.