Antioxidant activity of selenenamide-based mimic as a function of the aromatic thiols nucleophilicity, a DFT-SAPE model.

The mechanism of action of the selenenamide 1 as a mimic of the glutathione peroxidase (GPx) was investigated by the density functional theory. The solvent-assisted proton exchange procedure was applied to model the catalytic behavior and antioxidant activity of this mimic. To have an insight into the charge transfer effect, different aromatic thiols, including electron donating substituents on the phenyl ring were considered. The catalytic behavior of the selenenamide was modeled in a four-step mechanism, described by the oxidation of the mimic, the reduction of the obtained product, selenoxide, the reduction of the selenenylsulfide and dehydration of selenenic acid. On the basis of the activation parameters, the final step of the proposed mechanism is the rate determining states of the catalytic cycle. Turnover frequency (TOF) analysis showed that the electron donating groups at the para-position of the phenyl ring of the PhSH do not affect the catalytic activity of the selenenamide in contrast to p-methyl thiophenol which indicates the highest nucleophilicity. The evaluation of the electronic contribution of the various donating groups on the phenyl ring of the aromatic thiols shows that the antioxidant activity of the selenenamide sufficiently increases in the presence of the electron-donating substitutions. Finally, the charge transfer process at the rate-determining state was investigated based on the natural bond orbital analysis.

Computational Kinetic Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic: Effect of Nucleophilicity of Thiols on the Catalytic Activity.

The catalytic cycle of a new derivative of ebselen, 1, was elucidated via three steps by the density functional theory and solvent-assisted proton exchange procedure involving indirect proton exchange through a hydrogen-bonded transfer network. Different behaviors of the aromatic and aliphatic thiols were investigated in the reduction of selenoxide (step 2 → 3) and selenurane (step 3 → 1) based on their nucleophilicity. The reduction of selenoxide in the presence of thiophenol (ΔG‡ = 15.9 kcal·mol-1) is faster than that of methanethiol (ΔG‡ = 29.3 kcal·mol-1), and methanethiol makes the reduction of selenoxide unspontaneous and kinetically unfavorable (ΔG = 2.8 kcal·mol-1). The nucleophilic attack may be enhanced by using the thiophenol backbone at the selenium center to lower the energy barrier of the selenoxide reduction (ΔG‡ = 15.9 kcal·mol-1). On the basis of the turnover frequency calculations, during the catalytic cycle, the rate of the reaction was analyzed and discussed. Low values of the electron density and Laplacian at the transition states are the evidence of the covalent O-H and O-O bonds rupture in the presence of methanethiol and thiophenol. The nature of the critical bond points was characterized, using the quantum theory of atoms in molecules, based on the electron location function and localized orbital locator values. Finally, the charge transfer process at the rate-determining step was investigated based on the natural bond orbital analysis.

Computational Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic.

To elucidate the role of a derivative of ebselen as a mimic of the antioxidant selenoenzyme glutathione peroxidase, density functional theory and solvent-assisted proton exchange (SAPE) were applied to model the reaction mechanism in a catalytic cycle. This mimic plays the role of glutathione peroxidase through a four-step catalytic cycle. The first step is described as the oxidation of 1 in the presence of hydrogen peroxide, while selenoxide is reduced by methanthiol at the second step. In the third step of the reaction, the reduction of selenenylsulfide occurs by methanthiol, and the selenenic acid is dehydrated at the final step. Based on the kinetic parameters, step 4 is the rate-determining step (RDS) of the reaction. The bond strength of the atoms involved in the RDS is discussed with the quantum theory of atoms in molecules (QTAIM). Low value of electron density, ρ(r), and positive Laplacian values are the evidence for the covalent nature of the hydrogen bonds rupture (O30-H31, O33-H34). A change in the sign of the Laplacian, L(r), from the positive value in the reactant to a negative character at the transition state indicates the depletion of the charge density, confirming the N5-H10 and O11-Se1 bond breaking. The analysis of electron location function (ELF) and localized orbital locator (LOL) of the Se1-N5 and Se1-O11 bonds have been done by multi-WFN program. High values of ELF and LOL at the transition state regions between the Se, N, and O atoms display the bond formation. Finally, the main donor-acceptor interaction energies were analyzed using the natural bond orbital analysis for investigation of their stabilization effects on the critical bonds at the RDS.

Computational kinetic modeling of the selenol catalytic activity as the glutathione peroxidase nanomimic.

Density functional theory and solvent-assisted proton exchange methods have been applied for computational modeling of the catalytic cycle of selenol zwitterion anion from the kinetic and thermodynamic viewpoints. Selenol zwitterion anion has been represented as an effective glutathione peroxidase nanomimic. It reduces peroxides through a three-step pathway. In the first step, seleninic acid is produced through deprotonating of the selenol zwitterion anion in the presence of the hydrogen peroxide. Seleninic acid reacts with a thiol to form selenylsulfide in the second step. In the last step, selenylsulfide is reduced by the second thiol and regenerates selenolate anion through disulfide formation. Selenol zwitterion anion in comparison to more widely studied compounds such as ebselen has a good activity to react with hydrogen peroxide and producing seleninic acid. The energy barrier of this reaction is 11.7kcalmol-1 which is smaller than the reported enzyme mimics. Moreover, the reactions of seleninic acid and selenylsulfide with methanethiol, which is used as a nucleophile, are exothermic by -18.4 or -57.0kcalmol-1, respectively. Based on the global electron density transfer value of -0.507 e from the natural atomic charge analysis, an electronic charge depletion at the transition state (TS), electron-donor substitutions on the selenolate facilitates the reduction reaction, effectively. Finally, the nature of the bond formation/cleavage at the TS has been quantitatively described by using the topological analyses.