RESUMEN
Natural antioxidants have become the subject of many investigations due to the role that they play in the reduction of oxidative stress. Their main scavenging mechanisms concern the direct inactivation of free radicals and the coordination of metal ions involved in Fenton-like reactions. Recently, increasing attention has been paid to non-covalent inhibition of enzymes involved in different diseases by the antioxidants. Here, a computational investigation on the primary antioxidant power of (+)-catechin against the â¢OOH radical has been performed in both lipid-like and aqueous environments, taking into account the relevant species present in the simulated acid-base equilibria at the physiological pH. Hydrogen Atom Transfer (HAT), Single Electron Transfer (SET), and Radical Adduct Formation (RAF) mechanisms were studied, and relative rate constants were estimated. The potential inhibitory activity of the (+)-catechin towards the most important proteases from SARS-CoV-2, 3C-like (Mpro) and papain-like (PLpro) proteases was also investigated by MD simulations to provide deeper atomistic insights on the binding sites. Based on the antioxidant and antiviral properties also unravelled by comparison with other molecules having similar chemical scaffold, our results propose that (+)-CTc satisfies can explicate a dual action as antioxidant and antiviral in particular versus Mpro from SARS-CoV-2.
Asunto(s)
Antioxidantes , Catequina , Simulación de Dinámica Molecular , Inhibidores de Proteasas , SARS-CoV-2 , Catequina/química , Catequina/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/metabolismo , SARS-CoV-2/efectos de los fármacos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Antivirales/química , Antivirales/farmacología , Humanos , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Proteasas 3C de Coronavirus/químicaRESUMEN
Laccases (EC 1.10.3.2) are multicopper oxidases with the capability to oxidize diverse phenolic and non-phenolic substrates. While the molecular mechanism of their activity towards phenolic substrates is well-established, their reactivity towards non-phenolic substrates, such as polycyclic aromatic hydrocarbons (PAHs), remains unclear. To elucidate the oxidation mechanism of PAHs, particularly the activation mechanism of the sp2 aromatic C-H bond, we conducted a density functional theory investigation on the oxidation of two PAHs (anthracene and benzo[a]pyrene) using an extensive model of the T1 copper catalytic site of the fungal laccase from Trametes versicolor.
Asunto(s)
Antracenos , Benzo(a)pireno , Cobre , Lacasa , Oxidación-Reducción , Lacasa/metabolismo , Lacasa/química , Antracenos/química , Antracenos/metabolismo , Cobre/química , Cobre/metabolismo , Benzo(a)pireno/metabolismo , Benzo(a)pireno/química , Teoría Funcional de la Densidad , Modelos Moleculares , Polyporaceae/enzimología , Dominio Catalítico , Polyporales/enzimología , Polyporales/metabolismo , Trametes/enzimologíaRESUMEN
For the first time, ultrafiltration (UF) green membranes were prepared through a sustainable route by using PLA as a biopolymer and dihydrolevoclucosenone, whose trade name is Cyrene™ (Cyr), dimethyl isosorbide (DMI), and ethyl lactate (EL) as biobased solvents. The influence of physical-chemical properties of the solvent on the final membrane morphology and performance was evaluated. The variation of polymer concentration in the casting solution, as well as the presence of Pluronic® (Plu) as a pore former agent, were assessed as well. The obtained results highlighted that the final morphology of a membrane was strictly connected with the interplaying of thermodynamic factors as well as kinetic ones, primarily dope solution viscosity. The pore size of the resulting PLA membranes ranged from 0.02 to 0.09 µm. Membrane thickness and porosity varied in the range of 0.090-0.133 mm of 75-87%, respectively, and DMI led to the most porous membranes. The addition of Plu to the casting solution showed a beneficial effect on the membrane contact angle, allowing the formation of hydrophilic membranes (contact angle < 90°), and promoted the increase of pore size as well as the reduction of membrane crystallinity. PLA membranes were tested for pure water permeability (10-390 L/m2 h bar).
RESUMEN
The aim of this study was to explore the copigmentation effect of gallic acid on red wine color and to dissect its mechanism at the molecular level. Three-dimensional studies, e.g., in model wine, in real wine and in silico, and multiple indicators, e.g., color, spectrum, thermodynamics and phenolic dynamics, were employed. The results showed that gallic acid significantly enhanced the color quality and stability of red wine. Physico-chemical interactions and chemical transformations should be the most likely mechanism, and physico-chemical interactions are also a prerequisite for chemical transformations. QM calculations of the physico-chemical interactions proved that the binding between gallic acid and malvidin-3-O-glucoside is a spontaneous exothermic reaction driven by hydrogen bonding and dispersion forces. The sugar moiety of malvidin-3-O-glucoside and the phenolic hydroxyl groups of gallic acid affect the formation of hydrogen bonds, while the dispersion interaction was related to the stacking of the molecular skeleton.
Asunto(s)
Antocianinas , Color , Ácido Gálico , Glucósidos , Enlace de Hidrógeno , Termodinámica , Vino , Ácido Gálico/química , Vino/análisis , Glucósidos/química , Antocianinas/química , Teoría Cuántica , Fenoles/químicaRESUMEN
The copigmentation effect between malvidin-3-O-glucoside and caffeic acid was comprehensive inquiry on the model wine solution, theoretical simulation and real wine. Thermodynamic parameters were determined by UV/Visible spectroscopy and Isothermal titration calorimetry (ITC). Theoretical data were obtained employing a dispersion-corrected density functional approach. The effects in real wines were investigated by adding the caffeic acid during different fermentation periods. Results shown that the copigmentation reaction between caffeic acid and malvidin-3-O-glucoside is a spontaneous exothermic reaction driven by hydrogen bonding and dispersions forces. Computations show that the polyhydroxyl sugar moiety and phenolic hydroxyl groups are the key active sites. The addition of caffeic acid in post-alcohol fermentation samples evidences an improving color characteristics in the wine.
Asunto(s)
Antocianinas , Ácidos Cafeicos , Color , Glucósidos , Termodinámica , Vino , Ácidos Cafeicos/química , Vino/análisis , Glucósidos/química , Antocianinas/química , Enlace de Hidrógeno , Estructura Molecular , FermentaciónRESUMEN
A DFT and TDDFT study has been carried out on monomeric anthraquinones Emodin and Dermocybin (Em, Derm) recently proposed as natural antibacterial photosensitizers able to act also against gram-negative microbes. The computational study has been performed considering the relative amount of neutral and ionic forms of each compound in water, with the variation of pH. The occurrence of both Type I and Type II photoreactions has been explored computing the absorption properties of each species, the spin-orbit coupling constants (SOC), the vertical ionization potentials and the vertical electron affinities. The most plausible deactivation channels leading to the population of excited triplet states have been proposed. Our data indicate Emodin as more active than Dermocybin in antimicrobial photodynamic therapy throughout the Type II mechanism. Our data support a dual TypeI/II activity of the monomeric anthraquinones Emodin and Dermccybin in water, in all the considered protonation states.
Asunto(s)
Emodina , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Antraquinonas , Antibacterianos , AguaRESUMEN
The antioxidant power of quercetin-3-O-glucuronide (miquelianin) has been studied, at the density functional level of theory, in both lipid-like and aqueous environments. In the aqueous phase, the computed pKa equilibria allowed the identification of the neutral and charged species present in solution that can react with the â OOH radical. The Hydrogen Atom Transfer (HAT), Single Electron Transfer (SET) and Radical Adduct Formation (RAF) mechanisms were considered, and the individual, total and fraction corrected rate constants were obtained. Potential non-covalent inhibition of Mpro from SARS-CoV-2 by miquelianin has been also evaluated.
Asunto(s)
Antioxidantes , Proteínas M de Coronavirus , SARS-CoV-2 , Antioxidantes/química , Antioxidantes/farmacología , SARS-CoV-2/efectos de los fármacos , Quercetina/química , Quercetina/análogos & derivados , Quercetina/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Proteasas 3C de Coronavirus/química , Antivirales/química , Antivirales/farmacología , Teoría Funcional de la Densidad , Humanos , COVID-19/virologíaRESUMEN
The nonstructural protein 12, known as RNA-dependent RNA polymerase (RdRp), is essential for both replication and repair of the viral genome. The RdRp of SARS-CoV-2 has been used as a promising candidate for drug development since the inception of the COVID-19 spread. In this work, we performed an in silico investigation on the insertion of the naturally modified pyrimidine nucleobase ddhCTP into the SARS-CoV-2 RdRp active site, in a comparative analysis with the natural one (CTP). The modification in ddhCTP involves the removal of the 3'-hydroxyl group that prevents the addition of subsequent nucleotides into the nascent strand, acting as an RNA chain terminator inhibitor. Quantum mechanical investigations helped to shed light on the mechanistic source of RdRp activity on the selected nucleobases, and comprehensive all-atom simulations provided insights about the structural rearrangements occurring in the active-site region when inorganic pyrophosphate (PPi) is formed. Subsequently, the intricate pathways for the release of PPi, the catalytic product of RdRp, were investigated using Umbrella Sampling simulations. The results are in line with the available experimental data and contribute to a more comprehensive point of view on such an important viral enzyme.
Asunto(s)
COVID-19 , Citidina Trifosfato , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Replicación de ARN , ARN Viral , Antivirales/química , ARN Polimerasa Dependiente del ARN/metabolismoRESUMEN
Invited for the cover of this issue are Jesús Ferrando-Soria, Donatella Armentano, Antonio Leyva-Pérez, Emilio Pardo and co-workers at University of Valencia, Technical University of Valencia and University of Calabria. The image depicts the crystal structure of a novel ZnII biological metal-organic framework that mimics ß-lactamase enzymes. Read the full text of the article at 10.1002/chem.202301325.
Asunto(s)
Biomimética , Estructuras Metalorgánicas , Humanos , Catálisis , Penicilinas , beta-Lactamasas , Antibacterianos , ZincRESUMEN
Enzyme FAST-PETase, recently obtained by a machine learning approach, can depolymerize poly(ethylene terephthalate) (PET), a synthetic resin employed in plastics and in clothing fibers. Therefore it represents a promising solution for the recycling of PET-based materials. In this study, a model of PET was adopted to describe the substrate, and all-atoms classical molecular dynamics (MD) simulations on apo- and substrate-bound FAST-PETase were carried out at 30 and 50 °C to provide atomistic details on the binding step of the catalytic cycle. Comparative analysis shed light on the interactions occurring between the FAST-PETase and 4PET at 50 °C, the optimal working conditions of the enzyme. Pre-organization of the enzyme active and binding sites has been highlighted, while MD simulations of FAST-PETase:4PET pointed out the occurrence of solvent-inaccessible conformations of the substrate promoted by the enzyme. Indeed, neither of these conformations was observed during MD simulations of the substrate alone in solution performed at 30, 50 and 150 °C. The analysis led us to propose that, at 50 °C, the FAST-PETase is pre-organized to bind the PET and that the interactions occurring in the binding site can promote a more reactive conformation of PET substrate, thus enhancing the catalytic activity of the enzyme.
Asunto(s)
Hidrolasas , Tereftalatos Polietilenos , Dominio Catalítico , Hidrolasas/metabolismo , Temperatura , Dominios Proteicos , Sitios de Unión , Tereftalatos Polietilenos/químicaRESUMEN
In this work, we elucidated some key aspects of the mechanism of action of the cisplatin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5'-(2'-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2-3. The affinities of cisplatin metabolites 2-3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2-3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study's insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated.
Asunto(s)
Cisplatino , Guanina , Cisplatino/farmacología , Polimerasa Taq , Simulación de Dinámica Molecular , ADN/química , NucleótidosRESUMEN
ß-Lactam antibiotics are one of the most commonly prescribed drugs to treat bacterial infections. However, their use has been somehow limited given the emergence of bacteria with resistance mechanisms, such as ß-lactamases, which inactivate them by degrading their four-membered ß-lactam rings. So, a total knowledge of the mechanisms governing the catalytic activity of ß-lactamases is required. Here, we report a novel Zn-based metal-organic framework (MOF, 1), possessing functional channels capable to accommodate and interact with antibiotics, which catalyze the selective hydrolysis of the penicillinic antibiotics amoxicillin and ceftriaxone. In particular, MOF 1 degrades, very efficiently, the four-membered ß-lactam ring of amoxicillin, acting as a ß-lactamase mimic, and expands the very limited number of MOFs capable to mimic catalytic enzymatic processes. Combined single-crystal X-ray diffraction (SCXRD) studies and density functional (DFT) calculations offer unique snapshots on the host-guest interactions established between amoxicillin and the functional channels of 1. This allows to propose a degradation mechanism based on the activation of a water molecule, promoted by a Zn-bridging hydroxyl group, concertedly to the nucleophilic attack to the carbonyl moiety and the cleaving of C-N bond of the lactam ring.
Asunto(s)
Estructuras Metalorgánicas , beta-Lactamasas , beta-Lactamasas/química , Penicilinas , Biomimética , Antibacterianos/química , beta-Lactamas , Catálisis , Amoxicilina , Zinc/químicaRESUMEN
Lanmodulin (LanM) is the first identified macrochelator that has naturally evolved to sequester ions of rare earth elements (REEs) such as Y and all lanthanides, reversibly. This natural protein showed a 106 times better affinity for lanthanide cations than for Ca, which is a naturally abundant and biologically relevant element. Recent experiments have shown that its metal ion binding activity can be further extended to some actinides, like Np, Pu, and Am. For this reason, it was thought that LanM could be adopted for the separation of REE ions and actinides, thus increasing the interest in its potential use for industry-oriented applications. In this work, a systematic study of the affinity of LanM for lanthanides and actinides has been carried out, taking into account all trivalent ions belonging to the 4f (from La to Lu) and 5f (from Ac to Lr) series, starting from their chemistry in solution. On the basis of a recently published nuclear magnetic resonance structure, a model of the LanM-binding site was built and a detailed structural and electronic description of initial aquo- and LanM-metal ion complexes was provided. The obtained binding energies are in agreement with the available experimental data. A possible reason that could explain the origin of the affinity of LanM for these metal ions is also discussed.
RESUMEN
The effect on the photophysical properties of sulfur- and selenium-for-oxygen replacement in the skeleton of the oxo-4-dimethylaminonaphthalimide molecule (DMNP) has been explored at the density functional (DFT) level of theory. Structural parameters, excitation energies, singlet-triplet energy gaps (ΔES-T), and spin-orbit coupling constants (SOC) have been computed. The determined SOCs indicate an enhanced probability of intersystem crossing (ISC) in both the thio- and seleno-derivatives (SDMNP and SeDMNP, respectively) and, consequently, an enhancement of the singlet oxygen quantum yields. Inspection of Type I reactions reveals that the electron transfer mechanisms leading to the generation of superoxide is feasible for all the compounds, suggesting a dual Type I/Type II activity.
RESUMEN
In the present work, we report a computational study on some important chemical properties of the flavonoid isorhamnetin, used in traditional medicine in many countries. In the course of the study we determined the acid-base equilibria in aqueous solution, the possible reaction pathways with the â¢OOH radical and the corresponding kinetic constants, the complexing capacity of copper ions, and the reduction of these complexes by reducing agents such as superoxide and ascorbic anion by using density functional level of theory Density Functional Theory. Finally, the non-covalent inhibition ability of the SARS-CoV-2 main protease enzyme by isorhamnetin was examined by molecular dynamics (MD) and docking investigation.
RESUMEN
The structural characterization of a new flavonoid from bergamot fruit (Citrus bergamia Risso) carrying the 3-hydroxy-3-methyl glutaryl (HMG) ester moiety has been accomplished, and its antioxidant ability was tested from a chemical point of view. The peculiarity of the new molecule, named peripolin, relies on the presence of the HMG chemical group linked to the sugar portion of neoeriocitrin; the structure was elucidated using both high-resolution mass spectrometry and nuclear magnetic resonance experiments performed on the purified molecule extracted from the fruit. The antioxidant ability of the new molecule was tested by classical chemical approaches, such as DPPH, ABTS and FRAP assays, and from a theoretical point of view. 1H and 13C NMR experiments and HR-ESI-MS/MS experiments show unequivocally that the HMG moiety is linked to the primary position of the glucose unit of neohesperidose, while the chemical tests and the computational results show that peripolin possesses strong antioxidant behavior, similar to that of neoeriocitrin and remarkably higher respect to the other flavonoids present in the fruit. Furthermore, the quantitative assays carried out by UPLC-MS/MS showed that its amount in the fruit is similar to that of the other main flavonoids. Furthermore, molecular dynamics simulations allowed us to investigate the possible conformations adopted by the antioxidants in the presence of water molecules. In particular, the switch of open-closed conformations of HMG-containing species was evidenced. As far as the reaction with DPPH, the calculation of ΔGrea supported the experimental outcomes regarding the peripolin and neoeriocitrin activity. In conclusion, bergamot fruit, already known for its potential to lower the level of blood cholesterol, has been proven to contain molecules such as neoeriocitrin and the newly characterized peripolin, which could have important in-vivo antioxidant characteristics.
RESUMEN
The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 outbreak that is affecting the entire planet. As the pandemic is still spreading worldwide, with multiple mutations of the virus, it is of interest and of help to employ computational methods for identifying potential inhibitors of the enzymes responsible for viral replication. Attractive antiviral nucleotide analogue RNA-dependent RNA polymerase (RdRp) chain terminator inhibitors are investigated with this purpose. This study, based on molecular dynamics (MD) simulations, addresses the important aspects of the incorporation of an endogenously synthesized nucleoside triphosphate, ddhCTP, in comparison with the natural nucleobase cytidine triphosphate (CTP) in RdRp. The ddhCTP species is the product of the viperin antiviral protein as part of the innate immune response. The absence of the ribose 3'-OH in ddhCTP could have important implications in its inhibitory mechanism of RdRp. We built an in silico model of the RNA strand embedded in RdRp using experimental methods, starting from the cryo-electron microscopy structure and exploiting the information obtained by spectrometry on the RNA sequence. We determined that the model was stable during the MD simulation time. The obtained results provide deeper insights into the incorporation of nucleoside triphosphates, whose molecular mechanism by the RdRp active site still remains elusive.
Asunto(s)
COVID-19 , Citidina Trifosfato , ARN Polimerasa Dependiente del ARN , SARS-CoV-2 , Humanos , Antivirales/farmacología , Antivirales/química , Microscopía por Crioelectrón , Citidina Trifosfato/química , Simulación de Dinámica Molecular , Nucleósidos , Nucleótidos , Ribosa , ARN Viral , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , SARS-CoV-2/química , SARS-CoV-2/metabolismoRESUMEN
Thionation of carbonyl groups of known dyes is a rapidly emerging strategy to propose an advance toward heavy-atom-free photosensitizers to be used in photodynamic therapy (PDT). The sulfur-for-oxygen replacement has recently proved to enhance the singlet oxygen quantum yield of some existing fluorophores and to shift the absorption band at longer wavelengths. Drawing inspiration from this challenging evidence, the effect of both sulfur- and selenium-for-oxygen replacement in the skeleton of the oxo-4-dimethylamino-1,8-naphthalimide molecule (DMN) has been analyzed by means of a DFT study. The thio- and seleno-derivatives (SDMN and SeDMN, respectively) have been shown to offer the possibility to access a multitude of ISC (intersystem crossing) pathways involved in the triplet deactivation mechanisms with a consequent enhancement of the singlet oxygen production, also arising from the change of orbital type involved in the radiationless 1nπ* â 3ππ* transitions. Moreover, the change in nature from a 1ππ* to a 1nπ* observed in the SeDMN has been revealed to be crucial to reach more clinically useful regions of the spectrum suggesting that the selenium-for-oxygen replacement can be proposed as a strategy to achieve more suitable PDT agents while proposing an advance toward heavy-atom-free PSs.
Asunto(s)
Selenio , Oxígeno Singlete , Colorantes Fluorescentes , Naftalimidas , Oxígeno , Fármacos Fotosensibilizantes , Teoría Cuántica , AzufreRESUMEN
Both toxic and physiological effects of CO are mostly caused by well described interactions with heme-groups of proteins. Interactions of CO with non-heme proteins have also been unveiled. Besides interaction of CO with mitochondrial heme containing respiratory complexes, a BK channel and the phosphate carrier which do not contain metal cofactors, have been identified as CO targets. However, the molecular mechanisms of interaction with non-metal-containing proteins are not understood. We show in this work the effect of CO on the mitochondrial carnitine carrier (SLC25A20) using CORM-3, a widely recognized CO releasing compound. CO exerts an inhibitory effect at the micromolar concentration on the transport function of the transporter extracted from treated mitochondria. The effect is due to a single Cys residue, C136 as revealed by mass spectrometry analysis. A computational approach predicted the need for vicinal Asp and Lys residues for the C136 carbonylation to occur. These data demonstrate a novel mechanism of interaction of CO with a protein not containing metal atoms and will enable the prediction of CO targets.
Asunto(s)
Monóxido de Carbono , Compuestos Organometálicos , Monóxido de Carbono/metabolismo , Monóxido de Carbono/farmacología , Carnitina/análogos & derivados , Carnitina/metabolismo , Hemo/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Mitocondrias/metabolismo , Compuestos Organometálicos/farmacologíaRESUMEN
In this study, the scavenging activity against OOH radicals and the copper-chelating ability of two new synthesized molecules (named L1 and L2) that can act as multiple target agents against Alzheimer's disease have been investigated at the density functional theory level. The pKa and molar fractions at physiological pH have been predicted. The main antioxidant reaction mechanisms in lipid-like and water environments have been considered and the relative rate constants determined. The copper-chelating ability of the two compounds has also been explored at different coordination sites and computing the complexation kinetic constants. Results show the L1 compound is a more effective radical scavenging and copper-chelating agent than L2.