Molecular Docking Studies of Disubstituted Diaryl Diselenides as Mammalian δ-Aminolevulinic Acid Dehydratase Enzyme Inhibitors

Abstract

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.

Acknowledgments

We are thankful to CNPq (process no. 142611/2009-3), CAPES VITAE, FINEP, INCT-CNPQ for Excitoxicity and Neuroprotection, FAPERGS-PRONEX-CNPq, and IBNet-FINEP for providing financial support and fellowship to researchers, and to Scripps Research Institute and Accelrys, Inc., for providing free academic license of programs used in this study.