The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

Abstract

Organoselenium compounds present many pharmacological properties and are promising drugs. However, toxicological effects associated with inhibition of thiol-containing enzymes, such as the δ-aminolevulinic acid dehydratase (δ-AlaD), have been described. The molecular mechanism(s) by which they inhibit thiol-containing enzymes at the atomic level, is still not well known. The use of computational methods to understand the physical-chemical properties and biological activity of chemicals is essential to the rational design of new drugs. In this work, we propose an in silico study to understand the δ-AlaD inhibition mechanism by diphenyl diselenide (DPDS) and its putative metabolite, phenylseleninic acid (PSA), using δ-AlaD enzymes from Homo sapiens (Hsδ-AlaD), Drosophila melanogaster (Dmδ-AlaD) and Cucumis sativus (Csδ-AlaD). Protein modeling homology, molecular docking, and DFT calculations are combined in this study. According to the molecular docking, DPDS and PSA might bind in the Hsδ-AlaD and Dmδ-AlaD active sites interacting with the cysteine residues by Se … S interactions. On the other hand, the DPDS does not access the active site of the Csδ-AlaD (a non-thiol protein), while the PSA interacts with the amino acids residues from the active site, such as the Lys291. These interactions might lead to the formation of a covalent bond, and consequently, to the enzyme inhibition. In fact, DFT calculations (mPW1PW91/def2TZVP) demonstrated that the selenylamide bond formation is energetically favored. The in silico data showed here are in accordance with previous experimental studies, and help us to understand the reactivity and biological activity of organoselenium compounds. dehydratase (mδ-AlaD) or porphobilinogen synthase (PBGS) (EC 4.2.1.24). Since the δ-AlaD is an important enzyme involved in the porphyrins' synthesis, its inhibition can have toxicological consequences [8][9][10][11]. The δ-AlaD catalyzes the asymmetric condensation of two molecules of 5-aminolevulinic acid (δ-aminolevulinic acid -5-Ala), forming the porphobilinogen (PBG), which is the precursor of porphyrins' synthesis (Fig. 1B). In the enzyme active site, each substrate binds at two different subsites (A and P), leading to the regioselective product PBG. The acetic acid and propanoic acid side-chains of PBG originate from the subsites A and P, respectively [12][13][14]. Porphyrins are essential to living beings, particularly to the aerobic life, due to the heme prosthetic group, which is involved in the transport of oxygen (hemoglobin and myoglobin), xenobiotic metabolism (cytochrome P450), protection against peroxides (peroxidases and catalases), and chlorophyll synthesis [13,[15][16][17]. There are two major classes of δ-AlaD: the Zn-dependent enzymes (that are present in mammals, fungi

Toxicology and pharmacology of synthetic organoselenium compounds: an update

“…A very recent docking study was performed with sources of δ-ALA-D enzyme from Homo sapiens (Hsδ-AlaD), Drosophila melanogaster (Dmδ-AlaD), and Cucumis sativus (Csδ-AlaD), and the results corroborated the previous findings and provided more information about the mechanism of action (Nogara et al 2020 ). Nogara and collaborators also reported the interaction of diphenyl diselenide with the cysteine residues from Hsδ-AlaD and Dmδ-AlaD, but not with Csδ-AlaD (a non-thiol protein).…”

“…The active site of δ-ALA-D possesses three cysteine residues coordinated with Zn 2+ , which prevent the formation of disulfide bridges between the sulfhydryl groups. The proximity of the cysteine groups in the active site renders to enzyme a high sensitivity to oxidation (Nogara et al 2020 ; Rocha et al 2012c ; Saraiva et al 2012 ).…”

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Fig. 3 Additional proposed molecular mechanism showing the oxidation of catalytic cysteine (cys) 124 and 132 from human δ-ALAD by diphenyl diselenide, obtained by in silico studies (Nogara et al 2020 ; Saraiva et al 2012 )

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“…In the Dmδ-AlaD, selenium atoms interacted with arginine 205, proline 212, phenylalanine 204, tyrosine 20, and arginine 217 via H bond, and with the cysteine 122. Interestingly, they found that the diphenyl diselenide putative metabolite, phenylseleninic acid, as well as other oxidized organoselenium forms presented similar binding pose, interacting with the cysteine 124 and 122 residues from the active site from Hsδ-AlaD and Dmδ-AlaD, respectively (Nogara et al 2020 ).…”

Chalcogen-Nitrogen Bond: Insights into a Key Chemical Motif

“…Similar examples have been observed for the transcriptional regulator OhrR from Bacillus subtilis [40] and the murine receptor-like protein tyrosine phosphatase [41]. In addition, the formation of Se-N bond might be involved in the δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds [42].…”