Interplay between diphenyl diselenide and copper: Impact on D. melanogaster survival, behavior, and biochemical parameters.

Copper (Cu2+) is a biologically essential element that participates in numerous physiological processes. However, elevated concentrations of copper have been associated with cellular oxidative stress and neurodegenerative diseases. Organo­selenium compounds such as diphenyl diselenide (DPDS) have in vitro and in vivo antioxidant properties. Hence, we hypothesized that DPDS may modulate the toxicity of Cu2+ in Drosophila melanogaster. The acute effects (4 days of exposure) caused by a high concentration of Cu2+ (3 mM) were studied using endpoints of toxicity such as survival and behavior in D. melanogaster. The potential protective effect of low concentration of DPDS (20 µM) against Cu2+ was also investigated. Adult flies aged 1-5 days post-eclosion (both sexes) were divided into four groups: Control, DPDS (20 µM), CuSO4 (3 mM), and the combined exposure of DPDS (20 µM) and CuSO4 (3 mM). Survival, biochemical, and behavioral parameters were determined. Co-exposure of DPDS and CuSO4 increased acetylcholinesterase (AChE) activity and the generation of reactive oxygen species (ROS as determined by DFCH oxidation). Contrary to our expectation, the co-exposure reduced survival, body weight, locomotion, catalase activity, and cell viability in relation to control group. Taken together, DPDS potentiated the Cu2+ toxicity.

Molecular docking studies of disubstituted diaryl diselenides as mammalian δ-aminolevulinic acid dehydratase enzyme inhibitors.

δ-Aminolevulinic acid dehydratase (δ-ALAD) is a metalloprotein that catalyzes porphobilinogen formation. This enzyme is sensitive to pro-oxidants and classically used as a biomarker of lead (Pb) intoxication. Diphenyl diselenide [(PhSe)2] and analogs bis(4-chlorophenyl) diselenide [(pCl3PhSe)2], bis(4-methoxyphenyl)diselenide [(pCH3OPhSe)2], and bis[3-(trifluoromethy)phenyl] diselenide [(mCF3PhSe)2] inhibit mammalian δ-ALAD by oxidizing enzyme cysteinyl residues, which are involved in diselenide-induced toxicity. 2-Cysteinyl residues from δ-ALAD are believed to sequentially interact with (PhSe)2. Thus this study utilized protein-ligand docking analyses to determine which cysteinyl residues might be involved in the inhibitory effect of (PhSe)2 and analogs toward δ-ALAD. All diselenides that interact in a similar manner with the active site of δ-ALAD were examined. Docking simulations indicated an important role for π-π interactions involving Phe208 and cation-π interactions involving Lys199 and Arg209 residues with the aromatic ring of (PhSe)2 and analogs. Based upon these interactions an approximation between Se atoms and -SH of Cys124, with distances ranging between 3.3 Å and 3.5 Å, was obtained. These data support our previous postulations regarding the mechanism underlying δ-ALAD oxidation mediated by (PhSe)2 and analogs. Based on protein-ligand docking analyses, data indicated that -SH of Cys124 attacks one of the Se atoms of -SH of (PhSe)2 releasing one PhSeH (selenophenol). Subsequently, the -SH of Cys132 attacks the sulfur atom of Cys124 (from the bond of E-S-Se-Ph indermediate), generating the second PhSe⁻, and the oxidized and inhibited δ-ALAD. In conclusion, AutoDock Vina 1.1.1 was a useful tool to search for diselenides inhibitors of δ-ALAD, and, most importantly, it provided insight into molecular mechanisms involved in enzyme inhibition.