Dissociation of molecular aggregates under high hydrostatic pressure: the influence of water structure on Benzene cluster solubility

In some critical conditions water can solvate hydrophobic molecules, becoming a powerful solvent for nonpolar agents. To discuss the pressure effect on hydrated benzene clusters we carried out six consecutive 5000 ps (pico seconds) molecular dynamics simulations of benzene molecules in water cubic boxes at different pressure conditions, ranging from 1 bar to 5 kbar. Radius of gyration, diffusion coefficient, radial atomic pair distribution functions, number of hydrogen bonds between water molecules and the solvent accessible surface were monitored. Results showed that above 3 kbar the second hydration layer structure vanishes and the benzene clusters start to break up gradually. Up to 2 kbar, the solubility and diffusion of benzene molecules are inversely proportional to the increase of the pressure and above 3 kbar this behavior is inverted

Bonding, Structure, and Stability of Clusters: Some Surprising Results from an Experimental and Theoretical Investigation in Gas Phase

Structure and stability of clusters in the ground state were analyzed at the theoretical and experimental levels. Our experimental and theoretical findings showed that the clusters in gas phase tend to form mainly planar rings of four members. The symmetry and the small dipole moment in these specific configurations suggested that their stability could be associated with an alignment of the water molecules, maximizing attractive electrostatic interactions caused by changes in the charge distribution of the clusters

Biodegradation of Organophosphorus Compounds Predicted by Enzymatic Process Using Molecular Modelling and Observed in Soil Samples Through Analytical Techniques and Microbiological Analysis: A Comparison

Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for a period, suffering a degradation process where the biotic factors are considered the most relevant forms. However, to date, the biodegradation of OP compounds is not well understood. There are a plenty of structure-based biodegradation estimation methods, but none of them consider enzymatic interaction in predicting and better comprehending the differences in the fate of OPs in the environment. It is well known that enzymatic processes are the most relevant processes in biodegradation, and that hydrolysis is the main pathway in the natural elimination of OPs in soil samples. Due to this, we carried out theoretical studies in order to investigate the interactions of these OPs with a chosen enzyme—the phosphotriesterase. This one is characteristic of some soils’ microorganisms, and has been identified as a key player in many biodegradation processes, thanks to its capability for fast hydrolyzing of different OPs. In parallel, we conducted an experiment using native soil in two conditions, sterilized and not sterilized, spiked with specific amounts of two OPs with similar structure—paraoxon-ethyl (PXN) and O-(4-nitrophenyl) O-ethyl methylphosphonate (NEMP). The amount of OP present in the samples and the appearance of characteristic hydrolysis products were periodically monitored for 40 days using analytical techniques. Moreover, the number of microorganisms present was obtained with plate cell count. Our theoretical results were similar to what was achieved in experimental analysis. Parameters calculated by enzymatic hydrolysis were better for PXN than for NEMP. In soil, PXN suffered a faster hydrolysis than NEMP, and the cell count for PXN was higher than for NEMP, highlighting the higher microbiological toxicity of the latter. All these results pointed out that theoretical study can offer a better comprehension of the possible mechanisms involved in real biodegradation processes, showing potential in exploring how biodegradation of OPs relates with enzymatic interactions

A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B/NS3 from Dengue Virus

Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents

Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon

The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman’s modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood⁻brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies