title: 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.
authors.affiliation: Laboratório de Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus Universitário, Camobi, Santa Maria, RS, Brazil. rogerioaqsaraiva@hotmail.com
authors.forename: R A
authors.initials: RA
authors.lastname: Saraiva
authors.forename: D C
authors.initials: DC
authors.lastname: Bueno
authors.forename: P A
authors.initials: PA
authors.lastname: Nogara
authors.forename: J B T
authors.initials: JB
authors.lastname: Rocha
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D003198:Computer Simulation; D008322:Mammals / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D018036:Selenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D018036:Selenium Compounds; D000623:Porphobilinogen Synthase