ADME-Tox profiling of some low molecular weight water soluble chitosan derivatives

Within this study we use a few computational tools for predicting absorption, distribution, metabolism, excretion and toxicity (ADME-Tox), pharmacokinetics profiles, toxic/adverse effects, carcinogenicity, cardiotoxicity and endocrine disruption of some of low molecular weight water soluble derivatives of chitosan that are used in wound healing. Investigated compounds do not possess drug-like properties, their pharmacokinetics profiles reveal poor gastrointestinal absorption and low skin penetration. Chitosan derivatives cannot pass the blood-brain barrier and they are not able to inhibit the enzymes of the cytochrome P450 that are involved in the metabolism of xenobiotics. They do not reflect carcinogenicity and cardiotoxicity and reveal only a low probability to be endocrine disruptors. The main side effects in humans of the investigated compounds are: weight loss, acidosis, gastrointestinal toxicity, respiratory failure. This information is especially important for professional exposure and accidental contamination with these compounds

Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection

Within this study we have considered 9 triazole fungicides that are approved to be used in European Union for protecting cereals: cyproconazole, epoxiconazole, flutriafol, metconazole, paclobutrazole, tebuconazole, tetraconazole, triadimenol and triticonazole. We have summarized the few available data that support their effects on humans and used various computational tools to obtain a widely view concerning their possible harmful effects on humans. The results of our predictive study reflect that all triazole fungicides considered in this study reveal good oral bioavailability, are envisaged as being able to penetrate the blood brain barrier and to interact with P-glycoprotein and with hepatic cytochromes. The predictions concerning the toxicological endpoints for the investigated triazole fungicides reveal that they. reflect potential of skin sensitization, of blockage of the hERG K+ channels and of endocrine disruption, that they have not mutagenic potential and their carcinogenic potential is not clear. Epoxiconazole and triadimenol are predicted to have the highest potentials of producing numerous harmful effects on humans and their use should be avoided or limited

Exploring NMR ensembles of calcium binding proteins: Perspectives to design inhibitors of protein-protein interactions

<p>Abstract</p> <p>Background</p> <p>Disrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies. However, structural changes occurring at the binding interfaces make difficult drug discovery processes using structure-based drug design/virtual screening approaches. Here we focused on two homologous calcium binding proteins, calmodulin and human centrin 2, involved in different cellular functions via protein-protein interactions, and known to undergo important conformational changes upon ligand binding.</p> <p>Results</p> <p>In order to find suitable protein conformations of calmodulin and centrin for further structure-based drug design/virtual screening, we performed <it>in silico </it>structural/energetic analysis and molecular docking of terphenyl (a mimicking alpha-helical molecule known to inhibit protein-protein interactions of calmodulin) into X-ray and NMR ensembles of calmodulin and centrin. We employed several scoring methods in order to find the best protein conformations. Our results show that docking on NMR structures of calmodulin and centrin can be very helpful to take into account conformational changes occurring at protein-protein interfaces.</p> <p>Conclusions</p> <p>NMR structures of protein-protein complexes nowadays available could efficiently be exploited for further structure-based drug design/virtual screening processes employed to design small molecule inhibitors of protein-protein interactions.</p

Fractal dimension of the trajectory of a single particle diffusing in crowded media

Using Monte Carlo simulations we have modeled the diffusion of a single particle in twoand three-dimensional lattices with different crowding conditions given by distinct obstacles size and density. All registered data emphasize that diffusion process is anomalous and diffusing particle describes fractal trajectories. We have introduced a new time-scale fractal dimension, dm, which is related to the anomalous diffusion exponent, α. This allows us to relate the well-known length-scale fractal dimension of the random walk, dw, to the new one introduced here as a time-scale fractal dimension. Moreover, the 3D simulations consider similar conditions to those used in our previous FRAP experiments in order to reveal the relationship between the length and time-scale fractal dimensions

Monte Carlo simulation study of diffusion controlled reactions in three dimensional crowded media

Published data reveal that the rate coefficients of diffusion controlled reactions taking place in crowded media are time dependent. Within this study we have performed on lattice 3D Monte Carlo simulations concerning Michaelis-Menten enzymatic reactions in crowded media, such as the cyto- plasmatic region of the cells. We have considered the same size and mobility of the reactant particles and different crowding conditions using distinct concentrations and sizes of the immobile obstacles. The results we have obtained indicate a fractal like kinetics with the degree of fractality that changes with the concentration and dimension of the obstacles. The simulation data also reflect that, depending on the temporal scale, molecular crowding can bring positive or negative effects on reaction kinetics. Comparing the cases studied, for short periods of time the value of the initial rate constant generally increases with the degree of crowding. For longer periods of time and larger distances, molecular crowding slows down the reaction kinetics in every case, due to smaller diffusion coefficients of the reactants, having a more intense effect for the cases with higher degree of crowding

Solubility and ADMET profiles of short oligomers of lactic acid

Polylactic acid (PLA) is a polymer with an increased potential to be used in different medical applications, including tissue engineering and drug-carries. The use of PLA in medical applications implies the evaluation of the human organism\u27s response to the polymer inserting and to its degradation products. Consequently, within this study, we have investigated the solubility and ADMET profiles of the short oligomers (having the molecular weight lower than 3000 Da) resulting in degradation products of PLA. There is a linear decrease of the molar solubility of investigated oligomers with molecular weight. The results that are obtained also reveal that short oligomers of PLA have promising pharmacological profiles and limited toxicological effects on humans. These oligomers are predicted as potential inhibitors of the organic anion transporting peptides OATP1B1 and OATP1B3, they present minor probability to affect the androgen and glucocorticoid receptors, have a weak potential of hepatotoxicity, and may produce eye injuries. These outcomes may be used to guide or to supplement in vitro and/or in vivo toxicity tests such as to enhance the biodegradation properties of the biopolymer.</p

Aspects of fractal kinetics of enzymatic reactions by Monte Carlo simulations

Using Monte Carlo simulations in 3D media we investigate the effect of macromolecular crowding on biochemical reactions following a Michaelis-Menten kinetics. In the system substrate and product particles cannot overlap and the effect of crowders mobility and concentration are examined. The simulation data are analyzed in terms of parameters describing the time dependence of the rate coefficient. Our results indicate a fractal like kinetics with different degrees of fractality depending on crowders features. Even though small, when crowders mobility rises kinetics fractality decreases due to enhancement of diffusional movements of the reactants. Instead, increasing the crowders density in the system kinetics fractality presents a smooth growth as less free volume is available for reactants

Diffusion in macromolecular crowded media. Monte Carlo simulation of obstructed diffusion vs. FRAP experiments

The diffusion of tracer particles in 3D macromolecular crowded media has been studied using two methodologies, simulation and experimental, with the aim of comparing their results. Firstly, the diffusion of a tracer in an obstructed 3D lattice with mobile and big size obstacles has been analyzed through a Monte Carlo (MC) simulation procedure. Secondly, Fluorescence Recovery after Photobleaching (FRAP) experiments have been carried out to study the diffusion of a model protein (alpha-chymotrypsin) in in vitro crowded solution where two type of Dextran molecules are used as crowder agents. To facilitate the comparison the relative size between the tracer and the crowder is the same in both studies. The results indicate a qualitative agreement between the diffusional behaviors observed in the two studies. The dependence of the anomalous diffusion exponent and the limiting diffusion coefficient with the obstacle size and excluded volume shows, in both cases, a similar tendency. The introduction of a reduced mobility parameter in the simulation model accounting for the short range tracer-obstacle interactions allows to obtain a quantitative agreement between the limiting diffusion coefficient values yielded by both procedures. The simulation-experiment quantitative agreement for the anomalous diffusion exponent requires further improvements. As far as we know, this is the first reported work where both techniques are used in parallel to study the diffusion in macromolecular crowded media

New insights into diffusion in 3D crowded media by Monte Carlo simulations: Effect of size, mobility and spatial distribution of obstacles

Particle diffusion in crowded media was studied through Monte Carlo simulations in 3D obstructed lattices. Three particular aspects affecting the diffusion, not extensively treated in three-dimensional geometry, were analysed: the relative particle-obstacle size, the relative particle-obstacle mobility and the way of having the obstacles distributed in the simulation space (randomly or uniformly). The results are interpreted in terms of the parameters that characterize the time dependence of the diffusion coefficient: the anomalous diffusion exponent (), the crossover time from anomalous to normal diffusion regimes (τ) and the long time diffusion coefficient (D*). Simulation results indicate that there is a more anomalous diffusion (smaller ) and lower long time diffusion coefficient (D*) when obstacle concentration increases, and that, for a given total excluded volume and immobile obstacles, the anomalous diffusion effect is less important for bigger size obstacles. However, for the case of mobile obstacles, this size effect is inverted yielding values that are in qualitatively good agreement with in vitro experiments of protein diffusion in crowded media. These results underline that the pattern of the spatial partitioning of the obstacle-excluded volume is a factor to be considered together with the value of the excluded volume itself

The effects on human health of non-metallic, semimetals and heavy metals compounds generated by mining activities along the Serbian-Romanian border

This study makes an overview of the chemical pollutants, such as Be and its compounds, S and its compounds, P and its compounds, chlorine and chlorides, Na2O, K2O, Ti2O, CaO, MgO, CuO, SiO2, Al2O3, Fe2O3, Cr2O3, As2O3, that were registered in the mining operations areas in the cross-border region of Romania and Serbia. In addition, their possible effects on human health were discussed. Among the oxides, SiO2, Al2O3, Fe2O3 are the most abundant. From all these pollutants, the most health effects were registered for the compounds of P, S and Ca and the lowest number of health effects was recorded for chlorine. Among the human health effects that have been observed for these compounds, the most common are related to skin, eye and respiratory irritations in the case of acute exposure, but chronic exposure may lead to diseases affecting all the human organs. This information is important for population living in this area, due to air, water and soil pollution, but especially for professional exposure as workers in the mining operations are exposed to higher concentrations of pollutants and for long time