RESUMEN
The insecticidal property of ring C-seco limonoids has been discovered empirically and the target protein identified, but, to date, the molecular mechanism of action has not been described at the atomic scale. We elucidate on computational grounds whether nine C-seco limonoids present sufficiently high affinity to bind specifically with the putative target enzyme of the insects (ecdysone 20-monooxygenase). To this end, 3D models of ligands and the receptor target were generated and their interaction energies estimated by docking simulations. As a proof of concept, the tetrahydro-isoquinolinyl propenamide derivative QHC is the reference ligand bound to aldosterone synthase in the complex with PDB entry 4ZGX. It served as the 3D template for target modeling via homology. QHC was successfully docked back to its crystal pose in a one-digit nanomolar range. The reported experimental binding affinities span over the nanomolar to lower micromolar range. All nine limonoids were found with strong affinities in the range of -9 < ΔG < -13 kcal/mol. The molt hormone ecdysone showed a comparable ΔG energy of -12 kcal/mol, whereas -11 kcal/mol was the back docking result for the liganded crystal 4ZGX. In conclusion, the nine C-seco limonoids were strong binders on theoretical grounds in an activity range between a ten-fold lower to a ten-fold higher concentration level than insecticide ecdysone with its known target receptor. The comparable or even stronger binding hints at ecdysone 20-monooxygenase as their target biomolecule. Our assumption, however, is in need of future experimental confirmation before conclusions with certainty can be drawn about the true molecular mechanism of action for the C-seco limonoids under scrutiny.
Asunto(s)
Insecticidas , Limoninas , Oxigenasas , Insecticidas/farmacología , Ecdisona , Limoninas/farmacología , MudaRESUMEN
Polyethylene (PE) is one of the most highly consumed petroleum-based polymers and its accumulation as waste causes environmental pollution. In this sense, the use of microorganisms and their enzymes represents the most ecofriendly and effective decontamination approach. In this work, molecular docking simulation for catalytic enzyme degradation of PE was carried out using individual enzymes: laccase (Lac), manganese peroxidase (MnP), lignin peroxidase (LiP) and unspecific peroxygenase (UnP). PE-binding energy, PE-binding affinity and dimensions of PE-binding sites in the enzyme cavity were calculated in each case. Four hypothetical PE biodegradation pathways were proposed using individual enzymes, and one pathway was proposed using a synergic enzyme combination. These results show that in nature, enzymes act in a synergic manner, using their specific features to undertake an extraordinarily effective sequential catalytic process for organopollutants degradation. In this process, Lac (oxidase) is crucial to provide hydrogen peroxide to the medium to ensure pollutant breakdown. UnP is a versatile enzyme that offers a promising practical application for the degradation of PE and other pollutants due to its cavity features. This is the first in silico report of PE enzymatic degradation, showing the mode of interaction of PE with enzymes as well as the degradation mechanism.
Asunto(s)
Lacasa , Polietileno , Biodegradación Ambiental , Hongos , Lignina , Simulación del Acoplamiento MolecularRESUMEN
A theoretical study of the effect of the substituent Z on the gas phase acidity of substituted benzoic acids ZC6H4COOH in terms of density functional theory descriptors (chemical potential, softness and Fukui function) is presented. The calculated gas phase ΔacidG° values obtained were close to the experimental ones reported in the literature. The good relationship between the ΔacidG° values and the electronegativity of ZC6H4COOH and its fragments, suggested a better importance of the inductive than polarizability contributions. The balance of inductive and resonance contributions of the substituent in the acidity of substituted benzoic acids showed that the highest inductive and resonance effects were for the -SO2CF3 and -NH2 substituents in the para- and ortho-position, respectively. The Fukui function confirmed that the electron-releasing substituent attached to the phenyl ring of benzoic acid decreased the acidity in the trend ortho > meta > para, and the electron-withdrawing substituent increased the acidity in the trend ortho < meta < para.
Asunto(s)
Benzoatos/química , Teoría Funcional de la Densidad , Estructura MolecularRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative disorder associated with the aggregation of the amyloid-beta peptide (Aß) into large oligomers and fibrils that damage healthy brain cells. The predominant peptide fragments in the plaques are mainly formed by the Aß1-40 and Aß1-42 peptides, albeit the eleven-residue Aß25-35 segment is largely used in biological studies because it retains the neurotoxic properties of the longer Aß peptides. Recent studies indicate that treatment with therapeutic steroid hormones reduces the progress of the disease in AD models. Particularly, treatment with 17ß-aminoestrogens (AEs) has shown a significant alleviation of the AD development by inhibiting oxidative stress and neuronal death. Yet, the mechanism by which the AE molecules exhibit their beneficial effects remains speculative. To shed light into the molecular mechanism of inhibition of the AD development by AEs, we investigated the possibility of direct interaction with the Aß25-35 peptide. First, we calculate various interacting electronic properties of three AE derivatives as follows: prolame, butolame, and pentolame by performing DFT calculations. To account for the polymorphic nature of the Aß aggregates, we considered four different Aß25-35 systems extracted from AD relevant fibril structures. From the calculation of different electron density properties, specific interacting loci were identified that guided the construction and optimization of various complexes. Interestingly, the results suggest a similar inhibitory mechanism based on the direct interaction between the AEs and the M35 residue that seems to be general and independent of the polymorphic properties of the Aß aggregates. Our analysis of the complex formation provides a structural framework for understanding the AE therapeutic properties in the molecular inhibitory mechanism of Aß aggregation.
Asunto(s)
Péptidos beta-Amiloides/química , Estrógenos/farmacología , Agregado de Proteínas , Amino Alcoholes/química , Amino Alcoholes/farmacología , Estrenos/química , Estrenos/farmacología , Estrógenos/química , Modelos Moleculares , Agregado de Proteínas/efectos de los fármacos , Electricidad EstáticaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder caused by the aggregation of the amyloid-beta peptide (Aß) in senile plaques and cerebral vasculature. The Aß25-35 fraction has shown the most toxicity; its neurotoxic mechanisms are associated with the generation of oxidative stress and reactive astrogliosis that induce neuronal death and memory impairment. Studies indicate that pharmacological treatment with flavonoids reduces the rate of AD, in particular, it has been shown that antioxidants are compounds that could interact with this peptide due to their antioxidant proprieties. In this study, experimental and computational tools were used to calculate the molecular electrostatic potential and the Fukui function with the Gaussian 09 computational program, to predict the most reactive parts of these molecules and make the complex between Aß25-35 and two flavonoids (catechin and epicatechin) in the absolute gas-phase, where a possible interaction between them was observed. This is important for understanding the Aß25-35-Flavonoid (A-F) interaction as a therapeutic strategy to inhibit the neurotoxic effects that this peptide causes in AD, which currently is still considered an ambiguous process.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Antioxidantes/farmacología , Catequina/farmacología , Hipocampo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Animales , Muerte Celular/efectos de los fármacos , Hipocampo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Electricidad EstáticaRESUMEN
The nucleophilic character and stability of the carbanions vs. alkoxides derived from 2,2,2-trifluoro-1-(9-anthryl)ethanol and 1-(9-anthryl)ethanol containing X electron-releasing and X electron-acceptor substituents attached to C-10, have been studied at the B3LYP/6-31+G(d,p) level of theory. Results analyzed in terms of the absolute gas-phase acidity, Fukui function, the local hard and soft acids and bases principle, and the molecular electrostatic potential, show that the central ring of the 9-anthryl group confers an ambident nucleophilic character and stabilizes the conjugated carbanion by electron-acceptor delocalization.