Identification of Novel Nitrosative Stress Inhibitors through Virtual Screening and Experimental Evaluation.

Nitrosative and oxidative stress, associated with the generation of excessive reactive nitrogen and oxygen radical species respectively, are thought to contribute to protein misfolding diseases which represent a group of neurodegenerative disorders that are characterized by protein aggregation and plaque formation. Curcumin, a polyphenolic compound, possesses diverse anti-inflammatory, antitumor, and antioxidant properties. Several studies have revealed that curcumin can reduce the oxidative/nitrosative stress and thereby decrease the neuronal attrition. However, curcumin has poor bioavailability and has raised several concerns focused on its limited clinical impact. The aim of this study was to find other compounds which can assist in decreasing nitrosative stress and possess enhanced bioavailability. Here, use of ß-lactoglobulin was examined as a vehicle to transport molecules to the gut. The Zinc database was searched using curcumin as reference and 6457 compounds were selected for the study. These compounds were docked to ß-lactoglobulin using Glide to find the best fit ligands. Our studies identified four compounds that bind to ß-lactoglobulin and scavenge NOx (free radicals) efficiently.

Prediction of partial molar volumes of amino acids and small peptides: counting atoms versus topological indices.

Experimental data of partial molar volumes of amino acids and small peptides were compiled from several publications and enabled us to perform a predicative analysis based on quantitative structure-property relationships (QSPR). Based on the simplest level of the descriptors, the new method has high accuracy and was found to be more reliable when compared to the latter QSPR method based on topological indexes. Incorporation of isoelectric pH and 3-D solvent-accessible surface area parameters increased the predictability of the equation to a small extent. Cross-validation studies show that this method is successful in predicting the partial molar volumes of other noncoded amino acids, dipeptides, and diketopiperazine derivatives. This method is the beginning of new studies for larger peptides and proteins. It also can be suggested to be used for molecules that contain the same type of atoms as an amino acid.

Aromatic stabilization energy calculations for the antiaromatic fluorenyl cation. Issues in the choice of reference systems for positively charged species.

Aromatic stabilization energy (ASE) calculations for the fluorenyl cation show substantial destabilization in comparison to suitable reference systems (16.3 +/- 1.6 kcal/mol), supporting its categorization as an antiaromatic species. The choice of appropriate reference systems is exacting for cationic systems because of the need to match strain energies, convolved with allylic-type resonance terms and other potential structural effects that stabilize charge. Several homodesmotic ASE reaction systems are examined to demonstrate the role played by these factors in the calculation of an ASE value for the fluorenyl cation. The magnitudes of the derived ASE are quite similar for four very different determinative, homodesmotic reaction systems, giving strong support to the inherent accuracy of the final derived ASE value. The results of nucleus independent chemical shift calculations for the components of each one of the ASE reactions add additional weight to this conclusion.

Molecular Structure Parameters and Predictions of Enthalpies of Formation for Catacondensed and Pericondensed Polycyclic Aromatic Hydrocarbons.

Simple procedures that combine calculated ab initio theoretical energies with empirical structural parameters to correlate experimental enthalpies of formation for polycyclic aromatic hydrocarbons are evaluated for predictive potential. The analyzed data set consists of every benzenoid PAH with an experimentally determined DeltaH(f) degrees (g), i.e., nine catacondensed and three pericondensed aromatic compounds. The tested levels of theory use optimized STO-3G, 3-21G, and 6-31G calculated HF electronic energies, and energies determined at the correlated, optimized DFT B3LYP/6-31G and single point MP2/6-31G//HF/6-31G levels. The highest precision correlations of the DeltaH(f) degrees (g) data combine computed electronic energies with three types of parametrized carbon structure descriptors and a CH parameter. The predictive accuracy of this protocol is assessed using a statistical cross-validation procedure.