New insight into the role of glutathione reductase in glutathione peroxidase-like activity determination by coupled reductase model: Molecular docking study

Abstract Previously we have shown that among 15 substituted salicyloyl 5-seleninic acids (SSAs) 4 compounds with long side chains or a cyclohexyl group exhibit no glutathione peroxidase (GPx)-like activity in the coupled reductase model. Chemical reactions of one of the 4 inactive compounds with glutathione (GSH) and hydorperoxide, and experimental inhibition of glutathione reductase (GR) by the selenenylsulfide (RSeSG, the first intermediate in the catalytic cycle for GPx-like activity determination) of that inactive compound let us assess the interactions between 15 selenenylsulfide compounds and the active site of GR by molecular docking. Docking results showed that S and Se atoms in selenenylsulfides of the compounds with no GPx-like activity were beyond 5 A from S atom of Cys-58 and N atom of imidazole ring of His-467 (RMSDs for general assessment of 3 major distances were over 4.8 A), so that they could not be catalyzed to be reduced by GR. Furthermore, their docking scores over 89 Kcal/mol meant that the selenenylsulfides were bound too strongly to the active site of GR to leave from the site, leading eventually to inhibition of GR. We also applied such a molecular docking to ebselen, cyclic seleninate esters and di(propylaminomethylphenyl) diselenides to explain the discrepancies of their GPx-like activity, and suggested that the reduction of RSeSG by GR was important in GPx-like activity determination of GPx mimics and that the prediction of the possibility and the strength of GPx-like activity by using molecular docking should be done before experimental research.