A Comprehensive Study of the Radical Scavenging Activity of Rosmarinic Acid.

Rosmarinic acid (RA) is reported in separate studies to be either an inducer or reliever of oxidative stress, and this contradiction has not been resolved. In this study, we present a comprehensive examination of the radical scavenging activity of RA using density functional theory calculations in comparison with experimental data. In model physiological media, RA exhibited strong HO• radical scavenging activity with overall rate constant values of 2.89 × 1010 and 3.86 × 109 M-1 s-1. RA is anticipated to exhibit excellent scavenging properties for HOO• in an aqueous environment (koverall = 3.18 × 108 M-1 s-1, ≈2446 times of Trolox) following the hydrogen transfer and single electron transfer pathways of the dianion state. The neutral form of the activity is equally noteworthy in a lipid environment (koverall = 3.16 × 104 M-1 s-1) by the formal hydrogen transfer mechanism of the O6(7,15,16)-H bonds. Chelation with RA may prevent Cu(II) from reduction by the ascorbic acid anion (AA-), hence blocking the OIL-1 pathway, suggesting that RA in an aqueous environment also serves as an OIL-1 antioxidant. The computational findings exhibit strong concurrence with the experimental observations, indicating that RA possesses a significant efficacy as a radical scavenger in physiological environments.

Unleashing the power of boron: enhancing nitrogen reduction reaction through defective ReS2 monolayers.

Density functional theory (DFT) calculations were utilized to investigate the electrocatalytic potential of single boron (B) atom doping in defective ReS2 monolayers as an active site. Our investigation revealed that B-doped defective ReS2, containing S and S-Re-S defects, demonstrated remarkable conductivity, and emerged as an exceptionally active catalyst for nitrogen reduction reactions (NRR), exhibiting limiting potentials of 0.63 and 0.53 V, respectively. For both cases, we determined the potential by examining the hydrogenation of adsorbed N2* to N2H*. Although the competing hydrogen evolution reaction (HER) process appeared dominant in the S-Re-S defect case, its impact was minimal. The outstanding NRR performance can be ascribed to the robust chemical interactions between B and N atoms. The adsorption of N2 on B weakens the N-N bond, thereby facilitating the formation of NH3. Moreover, we verified the selectivity and stability of the catalysts for NRR. Our findings indicate that B-doped defective ReS2 monolayers hold considerable promise for electrocatalysis in a variety of applications.

Oversampling Free Energy Perturbation Simulation in Determination of the Ligand-Binding Free Energy.

Determination of the ligand-binding affinity is an extremely interesting problem. Normally, the free energy perturbation (FEP) method provides an appropriate result. However, it is of great interest to improve the accuracy and precision of this method. In this context, temperature replica exchange molecular dynamics implementation of the FEP computational approach, which we call replica exchange free energy perturbation (REP) was proposed. In particular, during REP simulations, the system can easily escape from being trapped in local minima by exchanging configurations with high temperatures, resulting in significant improvement in the accuracy and precision of protein-ligand binding affinity calculations. The distribution of the decoupling free energy was enlarged, and its mean values were decreased. This results in changes in the magnitude of the calculated binding free energies as well as in alteration in the binding mechanism. Moreover, the REP correlation coefficient with respect to experiment ( RREP = 0.85 ± 0.15) is significantly boosted in comparison with the FEP one ( RFEP = 0.64 ± 0.30). Furthermore, the root-mean-square error (RMSE) of REP is also smaller than FEP, RMSEREP = 4.28 ± 0.69 versus RMSEFEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc.

Theoretical and Experimental Studies of the Antioxidant and Antinitrosant Activity of Syringic Acid.

Syringic acid (SA) is a natural phenolic acid found in vegetables, fruits, and other plant-based foods. A range of biological activities were proposed for this compound including anticancer, antimicrobial, anti-inflammation, and anti-diabetic activities, as well as antioxidant and antinitrosant properties. In this study, the focus is on the latter two. The HO•, HOO•, NO, and NO2 scavenging activities of SA were evaluated in physiological environments by kinetic and thermodynamic calculations. The computed rate constants of the HO• radical scavenging of SA were 4.63 × 109 and 9.77 × 107 M-1 s-1 in polar and nonpolar solvents, respectively. A comparison with the experimentally determined rate constant in aqueous solution yields a kcalculated/kexperimental ratio of 0.3, thus the computed kinetic data are reasonably accurate. SA exhibited excellent HOO• and NO2 scavenging activity in water (koverall(HOO•) = 1.53 × 108 M-1 s-1 and koverall(NO2) = 1.98 × 108 M-1 s-1), whereas it did not show NO scavenging activity in any of the studied environments. In lipid medium, SA exhibited weak activity. Thus, in polar environments, the HOO• radical scavenging of SA is 1.53 times higher than that of ascorbic acid. Consistently, SA is a promising antioxidant and antinitrosant agent in polar environments.

Autodock Vina Adopts More Accurate Binding Poses but Autodock4 Forms Better Binding Affinity.

The binding pose and affinity between a ligand and enzyme are very important pieces of information for computer-aided drug design. In the initial stage of a drug discovery project, this information is often obtained by using molecular docking methods. Autodock4 and Autodock Vina are two commonly used open-source and free software tools to perform this task, and each has been cited more than 6000 times in the last ten years. It is of great interest to compare the success rate of the two docking software programs for a large and diverse set of protein-ligand complexes. In this study, we selected 800 protein-ligand complexes for which both PDB structures and experimental binding affinity are available. Docking calculations were performed for these complexes using both Autodock4 and Autodock Vina with different docking options related to computing resource consumption and accuracy. Our calculation results are in good agreement with a previous study that the Vina approach converges much faster than AD4 one. However, interestingly, AD4 shows a better performance than Vina over 21 considered targets, whereas the Vina protocol is better than the AD4 package for 10 other targets. There are 16 complexes for which both the AD4 and Vina protocols fail to produce a reasonable correlation with respected experiments so both are not suitable to use to estimate binding free energies for these cases. In addition, the best docking option for performing the AD4 approach is the long option. However, the short option is the best solution for carrying out Vina docking. The obtained results probably will be useful for future docking studies in deciding which program to use.

Hg2+-Promoted Spirolactam Hydrolysis Reaction: A Design Strategy for the Highly Selective Sensing of Hg2+ over other Metal Ions in Aqueous Media.

A mercury sensor (N-(rhodamine-6G)lactam-ethylenediamine-4-dimethylamino-cinnamaldehyde-RLED) based on the Hg2+-promoted hydrolysis reaction has been designed and developed with a combination of theoretical calculations and experimental investigations. The interaction between RLED and Hg2+ goes through a fast-initial stage with formation of a 1:1 complex, followed by a slow hydrolysis process. The formation of durable intermediate complexes is due to quite a long hydrolysis reaction time. As a result, RLED can selectively detect Hg2+ in the presence of other metal ions, with a detection limit of 0.08 µM for the colorimetric method, and of 0.008 µM with the fluorescent method. In addition, the RLED sensor can work in a solution with a small amount of organic solvent, with a wide pH range from 5 to 10. The time-dependent density functional theory has been used for investigations of the excitation and de-excitation processes in RLED, intermediate complexes, and reaction products, thereby clarifying the changes in the fluorescence intensity before and after the RLED interacts with Hg2+ ions.

Evaluation of Free Radical Scavenging Ability of Triazole-3-Thiol: A Combination of Experimental and Theoretical Approaches.

An assessment of the free radical scavenging potential of 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiol (AT) and 4-amino-5-(4-pyridyl)-4H-1,2,4-triazole-3-thiol (AP) involved a combination of experimental methodologies and theoretical calculations. In the 2,2-diphenyl-1-picrylhydrazyl (DPPH•) assay, AT exhibited an heightened efficacy in scavenging DPPH• radicals compared to AP. This was evidenced by the notably lower IC50DPPH value observed for AT (1.3 × 10-3 ± 0.2 × 10-3 M) in comparison to AP (2.2 × 10-3 ± 0.1 × 10-3 M). Similarly, in the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS• +) test, AT exhibited superior ability in neutralizing ABTS•+ free radical cations compared to AP, with the computed IC50ABTS values of 4.7 × 10-5 ± 0.1 × 10-5 M for AT and 5.5 × 10-5 ± 0.2 × 10-5 M for AP. Density functional theory served as the tool for evaluating the correlation between structural attributes and the antioxidant efficacy of the studied molecules. The findings highlighted the flexibility of hydrogen atoms within NH and NH2 groups to nucleophilic attacks, indicative of their pivotal role in the scavenging mechanism. Furthermore, investigations into the interactions between AT and AP with the free radical HOO• revealed predominantly the reaction via the hydrogen atom transfer mechanism. Both experimental observations and theoretical deductions collectively affirmed AT's superior free radical scavenging ability over AP in the gas phase and ethanol.

Advanced dual-atom catalysts on graphitic carbon nitride for enhanced hydrogen evolution via water splitting.

In this comprehensive investigation, we explore the effectiveness of 55 dual-atom catalysts (DACs) supported on graphitic carbon nitride (gCN) for both alkaline and acidic hydrogen evolution reactions (HER). Employing density functional theory (DFT), we scrutinize the thermodynamic and kinetic profiles of these DACs, revealing their considerable potential across a diverse pH spectrum. For acidic HER, our results identify catalysts such as FePd-gCN, CrCr-gCN, and NiPd-gCN, displaying promising ΔGH* values of 0.0, 0.0, and -0.15 eV, respectively. This highlights their potential effectiveness in acidic environments, thereby expanding the scope of their applicability. Within the domain of alkaline HER, this study delves into the thermodynamic and kinetic profiles of DACs supported on gCN, utilizing DFT to illuminate their efficacy in alkaline HER. Through systematic evaluation, we identify that DACs such as CrCo-gCN, FeRu-gCN, and FeIr-gCN not only demonstrate favorable Gibbs free energy change (ΔGmax) for the overall water splitting reaction of 0.02, 0.27, and 0.38 eV, respectively, but also feature low activation energies (Ea) for water dissociation, with CrCo-gCN, FeRu-gCN, and FeIr-gCN notably exhibiting the Ea of just 0.42, 0.33, and 0.42 eV, respectively. The introduction of an electronic descriptor (φ), derived from d electron count (Nd) and electronegativity (ETM), provides a quantifiable relationship with catalytic activity, where a lower φ corresponds to enhanced reaction kinetics. Specifically, φ values between 4.0-4.6 correlate with the lowest kinetic barriers, signifying a streamlined HER process. Our findings suggest that DACs with optimized φ values present a robust approach for the development of high-performance alkaline HER electrocatalysts, offering a pathway towards the rational design of energy-efficient catalytic systems.

Exploring the Multitarget Activity of Wedelolactone against Alzheimer's Disease: Insights from In Silico Study.

In this study, Wedelolactone's multitarget activity against Alzheimer's disease was examined using density functional theory and molecular docking techniques. At physiological pH, the pK a and molar fractions have been estimated. The most likely relative rate constants of two radical scavenger mechanisms are formal hydrogen transfer in a lipid environment and single-electron transfer in a water solvent. Compared to Trolox (k overall = 8.96 × 104 M-1 s-1), Wedelolactone (k overall = 4.26 × 109 M-1 s-1) is more efficient in scavenging the HOO• radical in an aqueous environment. The chelation capacity of metals was investigated by examining the complexation of the Cu(II) ion at various coordination positions and calculating the complexation kinetic constants. Furthermore, molecular docking simulations showed that the known forms of Wedelolactone at physiological pH effectively inhibited the AChE and BChE enzymes by comparing their activity to that of tacrine (control). Wedelolactone is a promising drug candidate for Alzheimer's disease therapy in light of these findings.

Antiradical Activity of Lignans from Cleistanthus sumatranus: Theoretical Insights into the Mechanism, Kinetics, and Solvent Effects.

Sumatranus lignans (SL) isolated from Cleistanthus sumatranus have demonstrated bioactivities, e.g., they were shown to exhibit immunosuppressive properties in previous research. Their structure suggests potential antioxidant activity that has not attracted any attention thus far. Consistently, a comprehensive analysis of the antioxidant activity of these compounds is highly desirable with the view of prospective medical applications. In this work, the mechanism and kinetics of the antiradical properties of SL against hydroperoxyl radicals were studied by using calculations based on density functional theory (DFT). In the lipid medium, it was discovered that SL reacted with HOO• through the formal hydrogen transfer mechanism with a rate constant of 101-105 M-1 s-1, whereas in aqueous media, the activity primarily occurred through the sequential proton loss electron transfer mechanism with rate constants of 102-108 M-1 s-1. In both lipidic and aqueous environments, the antiradical activity of compounds 6 and 7 exceeds that of resveratrol, ascorbic acid, and Trolox. These substances are therefore predicted to be good radical scavengers in physiological environments.

Oxoberberine: a promising natural antioxidant in physiological environments.

Oxoberberine (OB, 2,10-dihydroxy-3,9-dimethoxy-8-oxo-protoberberine, artathomsonine), which was isolated from Artabotrys thomsonii, was shown to exhibit potent antioxidant activity in vitro, however that is the only reported evidence of the radical scavenging activity of this compound thus far. In the present study, thermodynamic and kinetic calculations were used to determine the free radical scavenging activity of OB against a range of biologically important species, under physiological conditions. In the first part the activity is calculated against the HOO˙ radical that is both biologically important and a reference radical for comparison. It was found that OB has high antiradical capacity against HOO˙ in both lipid medium and water at physiological pH with k overall = 1.33 × 105 and 1.73 × 106 M-1 s-1, respectively. The formal hydrogen transfer mechanism defined the activity in nonpolar environments, whereas in the aqueous solution the single electron transfer competes with the hydrogen transfer pathway. The results showed that, in lipid medium, the HOO˙ trapping capability of OB is better than typical antioxidants such as Trolox, BHT, resveratrol and ascorbic acid. Similarly, the activity of OB in water at pH 7.4 is roughly 19 and 7 times faster than those of Trolox and BHT, respectively, but slightly lower than the activities of resveratrol or ascorbic acid. In the second part, it was found that OB also exhibits high activity against other typical free radicals such as CH3O˙, CH3OO˙, CCl3OO˙, NO2, SO4˙-, DPPH and ABTS˙+ with k f ranging from 2.03 × 105 to 5.74 × 107 M-1 s-1. Hence, it is concluded that OB is a promising radical scavenger in the physiological environment.

Insights into antiradical mechanism and pro-oxidant enzyme inhibitor activity of walterolactone A/B 6-O-gallate-ß-d-pyranoglucoside originating from Euonymus laxiflorus Champ. using in silico study.

The ability of a new compound, Wal, (walterolactone A/B 6-O-gallate-ß-d-pyranoglucoside) originating from Euonymus laxiflorus Champ. as a hydroperoxyl radical scavenger and pro-oxidant enzyme inhibitor was studied in silico. Different mechanisms, reaction locations, and chemical species of Wal in aqueous solution were taken into consideration. Formal hydrogen transfer from the OH group has been discovered as the chemical process that contributes most to the antioxidant properties of Wal in nonpolar and aqueous solutions. The overall rate coefficients for polar and non-polar environments are expected to have values of 7.85 × 106 M-1 s-1 and 4.84 × 105 M-1 s-1, respectively. According to the results of the investigation, Wal has greater scavenging activity against the HOO˙ radical than the reference antioxidant Trolox at physiological pH (7.4). In addition, docking results indicate that Wal's antioxidant properties involve the inhibition of the activity of enzyme families (CP450, MP, NO, and XO) that are responsible for ROS production.

Thermodynamics and kinetics in antibody resistance of the 501Y.V2 SARS-CoV-2 variant.

Understanding the thermodynamics and kinetics of the binding process of an antibody to the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein is very important for the development of COVID-19 vaccines. In particular, it is essential to understand how the binding mechanism may change under the effects of RBD mutations. In this context, we have demonstrated that the South African variant (B1.351 or 501Y.V2) can resist the neutralizing antibody (NAb). Three substitutions in the RBD including K417N, E484K, and N501Y alter the free energy landscape, binding pose, binding free energy, binding kinetics, hydrogen bonding, nonbonded contacts, and unbinding pathway of RBD + NAb complexes. The low binding affinity of NAb to 501Y.V2 RBD confirms the antibody resistance of the South African variant. Moreover, the fragment of NAb + RBD can be used as an affordable model to investigate changes in the binding process between the mutated RBD and antibodies.

Is natural fraxin an overlooked radical scavenger?

Fraxin (FX) (7-hydroxy-6-methoxycoumarin 8-glucoside) is a typical natural product of the coumarin family. This compound was shown to protect endothelial cells from oxidative stress; however, the nature of its antioxidant properties is still ambiguous. In this study, we report on a systematic evaluation of the radical scavenging activity of FX using a two-tier protocol based on thermodynamic and kinetic calculations. The results show that FX has moderate activity in the aqueous physiological environment against a range of radicals including HO˙, CCl3O˙, CCl3OO˙, NO2, , and HOO˙. The latter was examined in detail due to the prevalence of HOO˙ as a source of oxidative stress in biological systems. HOO˙ scavenging activity was promising in the gas phase but low in physiological environments with k overall = 1.57 × 106, 3.13 × 102 and 2.68 × 103 M-1 s-1 in the gas phase, pentyl ethanoate and water solvents, respectively. The formal hydrogen transfer mechanism at the O7-H bond dominates the hydroperoxyl radical scavenging of FX in the nonpolar media, whereas, in the polar environment, the activity is exerted by the single electron transfer mechanism of the anion state. This activity falls behind typical antioxidants such as Trolox, ascorbic acid, and trans-resveratrol under the studied conditions. Thus FX may have multiple health benefits, but it is not an outstanding natural antioxidant.

Binding of inhibitors to the monomeric and dimeric SARS-CoV-2 Mpro.

SARS-CoV-2 rapidly infects millions of people worldwide since December 2019. There is still no effective treatment for the virus, resulting in the death of more than one million patients. Inhibiting the activity of SARS-CoV-2 main protease (Mpro), 3C-like protease (3CLP), is able to block the viral replication and proliferation. In this context, our study has revealed that in silico screening for inhibitors of SARS-CoV-2 Mpro can be reliably done using the monomeric structure of the Mpro instead of the dimeric one. Docking and fast pulling of ligand (FPL) simulations for both monomeric and dimeric forms correlate well with the corresponding experimental binding affinity data of 24 compounds. The obtained results were also confirmed via binding pose and noncovalent contact analyses. Our study results show that it is possible to speed up computer-aided drug design for SARS-CoV-2 Mpro by focusing on the monomeric form instead of the larger dimeric one.

Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2.

The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempt to computationally screen for possible medications for COVID-19 via rapidly estimating the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twenty-seven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.

Radical Scavenging Activity of Natural Anthraquinones: a Theoretical Insight.

Anthraquinones (ANQs) isolated from Paederia plants are known to have antidiarrheal, antitussive, anthelmintic, analgesic, anti-inflammatory, antihyperlipidemic, antihyperglycaemic, and antimicrobial activities. The antioxidant properties were also noted but not confirmed thus far. In this study, the superoxide and hydroperoxide radical scavenging activities of six ANQs were evaluated using a computational approach. The results suggest that the ANQs exhibit low HOO• antiradical activity in all environments, including the gas phase (k < 102 M-1 s-1). In contrast, the ANQs might exert excellent O2 •- radical scavenging activity, particularly in aqueous solution. The rate constants of the superoxide anion scavenging in water (at pH = 7.4) range from 3.42 × 106 to 3.70 × 108 M-1 s-1. Compared with typical antioxidants such as ascorbic acid and quercetin, the superoxide anion scavenging activity of ANQs is significantly higher. Thus, the ANQs are promising O2 •- radical scavengers in polar media.

In Silico Evaluation of the Radical Scavenging Mechanism of Mactanamide.

Mactanamide (MA) is a diketopiperazine isolated from marine fungi of the genus Aspergillus. This compound is known as a natural antioxidant from experimental studies, yet this activity has not been successfully modeled thus far. In this work, the hydroperoxyl radical scavenging activity of MA was evaluated in the gas phase and physiological environments by thermodynamic and kinetic calculations. The results revealed that the HOO• radical scavenging of MA in the lipid media follows the formal hydrogen transfer mechanism via hydrogen abstraction at the O11-H bond. In the aqueous solution, however, the antioxidant activity follows the sequential proton loss electron transfer mechanism. The rate constant of the HOO• scavenging of MA in the polar environment is about 1045 times (k overall = 2.23 × 106 M-1 s-1) higher than that in the lipid medium (k overall = 2.20 × 103 M-1 s-1). In polar media, the HOO• radical scavenging activity of MA is therefore 18 times higher than that of Trolox, the reference compound when assessing antioxidant activity. The results presented here align well with the experimental data, validating the mechanistic pathways and thus providing useful insights into the antioxidant activity of MA.

A thermodynamic and kinetic study of the antioxidant activity of natural hydroanthraquinones.

Novel hydroanthraquinones isolated from marine algal-derived endophytic fungus Talaromyces islandicus EN-501 exhibited promising antioxidant properties in preliminary studies, raising the prospect of adapting these compounds for therapeutic use in diseases caused by oxidative stress. For medicinal applications it is beneficial to develop a full understanding of the antioxidant activity of these compounds. In this study, the hydroperoxide radical scavenging activity of five natural hydroanthraquinones was evaluated by kinetic and thermodynamic calculations. The results showed that the radical scavenging of these hydroanthraquinones in the gas phase and in lipid solvents was defined by the formal hydrogen transfer mechanism, that for the polar environments was decided by the sequential proton loss electron transfer pathway. The hydroanthraquinones exhibited good hydroperoxide scavenging activity in both polar and non-polar media. The overall rate constant values for the radical scavenging reaction were in the range of 3.42 × 101 to 2.60 × 105 M-1 s-1 and 3.80 × 106 to 5.87 × 107 M-1 s-1 in pentyl ethanoate and water solvents, respectively. Thus the activity of 8-hydroxyconiothyrinone B (1) is about 2.6 and 444.6 times higher than that of Trolox in the studied solvents, identifying 8-hydroxyconiothyrinone B as a promising antioxidant.

Pivotal Role of Heteroatoms in Improving the Corrosion Inhibition Ability of Thiourea Derivatives.

1,3-Diphenyl-2-thiourea (DPTU) and 1-phenyl-3-(2-pyridyl)-2-thiourea (PPTU) were selected as the researched subject for investigating the effect of heteroatoms on the low carbon steel corrosion inhibition ability. Results from the potentiodynamic polarization measurements (PPM) indicate that the addition of a nitrogen atom in the benzene ring increases the corrosion inhibition efficiency of PPTU (97.2%), being higher than that of DPTU (93.1%) at the same condition of 2.0 × 10-4 M at 30 °C. The Nyquist diagrams show that increasing the concentrations of both DPTU and PPTU will enhance the charge-transfer resistance and reduce the double-layer capacitance. The obtained data based on PPM and electrochemical impedance spectroscopy methods are in accordance to the analysis based on the scanning electrochemical microscopy images. Besides, results from quantum chemical calculations prove that the heteroatoms in the inhibitor molecules are the adsorption centers, and the benzene rings increase the electrostatic interaction between the inhibitor molecules and the steel surface. Results from Monte Carlo and molecular dynamics simulation have clarified the adsorption mechanism of DPTU and PPTU on the steel surface. Adsorption energies confirm that PPTU displays the higher inhibition ability as compared with DPTU.