Thiol modifier effects of diphenyl diselenides: insight from experiment and DFT calculations

A combination of spectroscopic, chromatographic and computational approaches was employed to investigate the reaction of several diselenides of formula (R-PhSe)(2) (R = CH3O, CH3, H, Cl, CF3) with a thiolate nucleophile, leading to the breaking of the selenium-selenium (Se-Se) bond. This process has fundamental importance in biological environments and provides a rationale to analyze the so-called thiol modifier effect of diselenides, which may be exploited in pharmacology and toxicology. Our data suggest that withdrawing substituents favor the reaction, effectively making the reaction energy more negative, but strong electron-withdrawing groups also prompt structural modification on the starting reactant, increasing the reaction barrier. Thus, the nature (electron rich or electron poor) of the diselenides can play an essential role in the reactivity and biological activity of these molecules

Effect of Methylmercury Binding on the Peroxide-Reducing Potential of Cysteine and Selenocysteine

Methylmercury (CH3Hg+) binding to catalytically fundamental cysteine and selenocysteine of peroxide-reducing enzymes has long been postulated as the origin of its toxicological activity. Only very recently, CH3Hg+ binding to the selenocysteine of thioredoxin reductase has been directly observed [ Pickering, I. J. et al. Inorg. Chem., 2020, 59, 2711-2718 ], but the precise influence of the toxicant on the peroxide-reducing potential of such a residue has never been investigated. In this work, we employ state-of-the-art density functional theory calculations to study the reactivity of molecular models of the free and toxified enzymes. Trends in activation energies are discussed with attention to the biological consequences and are rationalized within the chemically intuitive framework provided by the activation strain model. With respect to the free, protonated amino acids, CH3Hg+ binding promotes oxidation of the S or Se nucleus, suggesting that chalcogenoxide formation might occur in the toxified enzyme, even if the actual rate of peroxide reduction is almost certainly lowered as suggested by comparison with fully deprotonated amino acids models

Mechanistic insight into sars‐cov‐2 mpro inhibition by organoselenides: The ebselen case study

The main protease (Mpro) of SARS‐CoV‐2 is a current target for the inhibition of viral replication. Through a combined Docking and Density Functional Theory (DFT) approach, we investigated in‐silico the molecular mechanism by which ebselen (IUPAC: 2‐phenyl‐1,2‐ benzoselenazol‐3‐one), the most famous and pharmacologically active organoselenide, inhibits Mpro. For the first time, we report on a mechanistic investigation in an enzyme for the formation of the covalent ‐S‐Se‐ bond between ebselen and a key enzymatic cysteine. The results highlight the strengths and weaknesses of ebselen and provide hints for a rational drug design of bioorganic selenium‐based inhibitors

In the Chalcogenoxide Elimination Panorama: Systematic Insight into a Key Reaction

The selenoxide elimination is a well-known reaction in organochalcogen chemistry, with wide synthetic, biological, and toxicological implications. In this work, we apply benchmarked density functional theory (DFT) calculations to investigate different aspects of the title reaction in three (bio)chemically relevant models, spanning minimal systems of theoretical interests as well as biological or synthetic organochalcogenides. The activation strain analysis (ASA) methodology is employed along a suitable reaction coordinate to obtain insight into the role of the chalcogen and of the oxidation state, to pinpoint the factors that tune the elimination reactivity of the investigated systems. Lastly, we computationally validate the hypothesis that telluroxides eliminate more slowly than selenoxides because of a detrimental hydration process that leads to unreactive hydrates

Methylmercury Can Facilitate the Formation of Dehydroalanine in Selenoenzymes: Insight from DFT Molecular Modeling

Experimental studies have indicated that electrophilic mercury forms (e.g., methylmercury, MeHg+) can accelerate the breakage of selenocysteine in vitro. Particularly, in 2009, Khan et al. (Environ. Toxicol. Chem. 2009, 28, 1567-1577) proposed a mechanism for the degradation of a free methylmercury selenocysteinate complex that was theoretically supported by Asaduzzaman et al. (Inorg. Chem. 2010, 50, 2366-2372). However, little is known about the fate of methylmercury selenocysteinate complexes embedded in an enzyme, especially in conditions of oxidative stress in which methylmercury target enzymes operate. Here, an accurate computational study on molecular models (level of theory: COSMO-ZORA-BLYP-D3(BJ)/TZ2P) was carried out to investigate the formation of dehydroalanine (Dha) in selenoenzymes, which irreversibly impairs their function. Methylselenocysteine as well as methylcysteine and methyltellurocysteine were included to gain insight on the peculiar behavior of selenium. Dha forms in a two-step process, i.e., the oxidation of the chalcogen nucleus followed by a syn-elimination leading to the alkene and the chalcogenic acid. The effect of an excess of hydrogen peroxide, which may lead to the formation of chalcogenones before the elimination, and of MeHg+, a severe toxicant targeting selenoproteins, which leads to the formation of methylmercury selenocysteinate, are also studied with the aim of assessing whether these pathological conditions facilitate the formation of Dha. Indeed, elimination occurs after chalcogen oxidation and MeHg+ facilitates the process. These results indicate a possible mechanism of toxicity of MeHg+ in selenoproteins

Model Study on the Catalytic Cycle of Glutathione Peroxidase Utilizing Selenocysteine-Containing Tripeptides: Elucidation of the Protective Bypass Mechanism Involving Selenocysteine Selenenic Acids

Although much attention has been paid to chemical elucidation of the catalytic cycle of glutathione peroxidase (GPx), it has been hampered by instability of selenocysteine selenenic acid (SecSeOH) intermediates. In this study, not only chemical processes of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of a SecSeOH to the corresponding fivemembered ring selenenyl amide were demonstrated experimentally by utilizing selenopeptide model systems in which reactive intermediates can be stabilized by a nano-sized molecular cradle. The resulting cyclic selenenyl amide exhibited higher durability under oxidative conditions than in the state of a SecSeOH, corroborating its role as the protective form of GPx. The cyclization of SecSeOHs of the Sec-Gly-Thr and Sec-Gly-Lys models, which mimic the catalytic site of isozymes GPx1 and GPx4, respectively, was found to proceed at lower temperature than in the Sec-Gly-Gly model, which corresponds to the generalized form of the tripeptides in the catalytic site of GPx. The role of the hydrogen-bond accepting moieties in the cyclization process was elucidated by DFT calculation. It was indicated that, if the selenocysteine centers are incorporated in appropriate microenvironments, the bypass mechanism can function efficiently

The Potential of Ebselen Against Bipolar Disorder: A Perspective on the Interaction with Inositol Monophosphatase (IMPase)

Despite its narrow therapeutic index and the toxicity issues related to renal injuries, lithium is still a first-line choice for the treatment of mania and for preventing recurrences in bipolar disorder. Nevertheless, side effects and limited efficacy in some of the cases push the search for novel tools to ameliorate these conditions, which still represent a social burden, and great efforts are being made toward the identification of alternative therapeutic options. In this context, rational drug design, drug repurposing, and computer-aided drug discovery represent time-saving and efficient strategies to pursue this goal. Inositol monophosphatase (IMPase) represents the molecular target of lithium which acts as an uncompetitive inhibitor. In this context, a screening on NIH Clinical Collection of drug-like compounds highlighted the polypharmacological drug ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) as a non-competitive, irreversible IMPase inhibitor, suggesting that this molecule could represent a valid therapeutic alternative. In this perspective article, we aim at providing a historical overview of the uses of ebselen with particular attention to its potential use as lithium-mimetic. We critically analyse this aspect by investigating in silico the molecular mechanism leading to the formation of the Se-S bond between IMPase Cys141 and ebselen. Evidence of the bond formation is supported by the crystallographic data Fenn et al. We hypothesize that the IMPase-ebselen complex promotes the association with other IMPase chains, improving the formation of the tetramer adduct, suggesting that ebselen may stabilize the human IMPase in a form that could be less active, resulting in a decreased enzymatic activity

Chalcogen\u2013mercury bond formation and disruption in model Rabenstein's reactions: A computational analysis

Methylmercury is a highly toxic compound and human exposure is mainly related to consumption of polluted fish and seafood. The inactivation of thiol-based enzymes, promoted by the strong affinity binding of electrophilic mercuric ions to thiol and selenol groups of proteins, is likely an important factor explaining its toxicity. A key role is played by the chemistry and reactivity of the mercury\u2013chalcogens bond, particularly Hg-S and Hg-Se, which is the focus of this computational work (level of theory: (COSMO)-ZORA-BLYP-D3(BJ)/TZ2P). We analyze nine ligand-exchange model reactions (the so-called Rabenstein's reactions) involving an entering ligand (methylchalcogenolate) and a substrate (methylchalcogenolatemethylmercury). Trends in reaction and activation energies are discussed and a change in mechanism is reported for all cases when going from gas phase to water, that is, from a single-well potential energy surface (PES) to a canonical SN2-like mechanism. The reasons accounting for the biochemically challenging and desired displacement of methylmercury from a seleno/thiol protein can be found already in these model reactions, as can be seen from the similarities of the ligand exchange reactions in solution in thermodynamics and kinetics

Chalcogen-nitrogen bond: Insights into a key chemical motif

Chalcogen-nitrogen chemistry deals with systems in which sulfur, selenium, or tellurium is linked to a nitrogen nucleus. This chemical motif is a key component of different functional structures, ranging from inorganic materials and polymers, to rationally designed catalysts, to bioinspired molecules and enzymes. The formation of a selenium–nitrogen bond, typically occurring upon condensation of an amine and the unstable selenenic acid, often leading to intramolecular cyclizations, and its disruption, mainly promoted by thiols, are rather common events in organic Se-catalyzed processes. In this work, focusing on examples taken from selenium organic chemistry and biochemistry, the selenium–nitrogen bond is described, and its strength and reactivity are quantified using accurate computational methods applied to model molecular systems. The intermediate strength of the Se–N bond, which can be tuned to necessity, gives rise to significant trends when comparing it to the stronger S– and weaker Te–N bonds, reaffirming also in this context the peculiar and valuable role of selenium in chemistry and life