CORAL: binary classifications (active/inactive) for Liver-Related Adverse Effects of Drugs.

Classification data related to the Liver-Related Adverse Effects of Drugs have been studied with the CORAL software (http://www.insilico.eu/coral). Two datasets which contain compounds with two serum enzyme markers of liver toxicity: alanine aminotransferase (ALT, n=187) and aspartate aminotransferase (AST, n=209) are analyzed. Statistical quality of the prediction for ALT activity is n=35, Sensitivity = 0.5556, Specificity = 0.8077, and Accuracy = 0.7429. In the case of AST activity the prediction is characterized by n=42, Sensitivity = 0.6875, Specificity = 0.7692, and Accuracy = 0.7381. A number of structural alerts which can be related to the studied activities are revealed. It is the first attempt to build up the classification QSAR model by means of the Monte Carlo technique based on representation of the molecular structure by SMILES using the CORAL software.

Structure-activity relationship investigations of leishmanicidal N-benzylcytisine derivatives.

In vitro leishmanicidal activity of 16 N-benzylcytisine derivatives has been evaluated using Leishmania donovani axenic amastigotes. In general, halogen (bromo-, chloro-) derivatives appeared to be more toxic against parasites than their parent compounds. Quantum-chemical calculations helped to recognize certain patterns in the structure of frontier orbitals related to bioactivity of compounds. Thus, the presence of halogen atom is shown to have a significant effect on both distribution and the energy of LUMOs thereby on potent activity that was also confirmed by Quantitative-Structure Activity Relationship (QSAR) analysis. Experimentally and theoretically observed structure-cytotoxicity relationships are described.

Choosing safe dispersing media for C60 fullerenes by using cytotoxicity tests on the bacterium Escherichia coli.

Assessment of C(60) nanotoxicity requires a variety of strategies for dispersing it into biological systems. Our objective was to determine organic solvent/surfactant combinations suitable for this purpose. We used Escherichia coli (ATCC# 25254) to determine the cytotoxicity of C(60) in solvents at concentrations up to 100 ppm. In this preliminary study we hypothesized that C(60) toxicity is directly correlated with its degree of dispersion in solution and that more solubilizing solvents induce higher toxicity. Test solvent concentration (1%) and Tween 80 (0.04%) were based on E. coli viability assay. Sonication was used to further enhance C(60) dispersal. The end-point response was measured with viability (in terms of LC(50)) and general metabolic activity (in terms of IC(50)) of E. coli cultures after exposure. The ultimate goal was to select safe dispersing media and enrich the database of C(60) nanotoxicity for NanoQuantitative-Structure-Activity-Relationship (NanoQSAR) applications. LC(50) range was 30 ppm to >400 ppm. IC(50) followed the trend. Among the six solvent combinations, DMSO combined with Tween 80 was the optimum combination for defining a dose-response relationship for assessing its toxicity to E. coli. However, N,N-dimethylformamide has the greatest potential to be a safe solvent for C(60) applications based upon its biocompatibility. Solvent solubility alone could not account for the cytotoxicity observed in this study.

QSAR modeling of acute toxicity by balance of correlations.

Optimal descriptors based on the simplified molecular input line entry system (SMILES) have been utilized in modeling of acute toxicity towards rats. Toxicity of 61 benzene derivatives has been modeled by means of balance of correlations for sets of the training (n=27) and calibration (n=24). The obtained models were evaluated with the external test set (n=10). Comparison of models based on the balance of correlations and models which were obtained on base of the total training (i.e., in case of utilization both training and calibration sets as the united training set) has shown that the balance of correlations gives improvement of statistical quality for the external test set. Predictions based on the one-variable model (based on the correlation balance) are better that the results obtained by the multiple linear regression analysis based on topological and quantum chemical descriptors. A QSAR analysis showed that the electronegativity of the molecule plays an important role in acute toxicity of benzene derivatives studied; presence of electronegative groups increasing toxicity. The presence of nitrogen-containing groups (mostly NH groups) increasing the toxicity that confirmed by both approaches.

Aconitum and Delphinium sp. alkaloids as antagonist modulators of voltage-gated Na+ channels. AM1/DFT electronic structure investigations and QSAR studies.

Early pharmacological studies of Aconitum and Delphinium sp. alkaloids suggested that these neurotoxins act at site 2 of voltage-gated Na(+) channel and allosterically modulate its function. Understanding structural requirements for these compounds to exhibit binding activity at voltage-gated Na(+) channel has been important in various fields. This paper reports quantum-chemical studies and quantitative structure-activity relationships (QSARs) based on a total of 65 natural alkaloids from two plant species, which includes both blockers and openers of sodium ion channel. A series of 18 antagonist alkaloids (9 blockers and 9 openers) have been studied using AM1 and DFT computational methods in order to reveal their structure-activity (structure-toxicity) relationship at electronic level. An examination of frontier orbitals obtained for ground and protonated forms of the compounds revealed that HOMOs and LUMOs were mainly represented by nitrogen atom and benzyl/benzoylester orbitals with -OH and -OCOCH(3) contributions. The results obtained from this research have confirmed the experimental findings suggesting that neurotoxins acting at type 2 receptor site of voltage-dependent sodium channel are activators and blockers with common structural features and differ only in efficacy. The energetic tendency of HOMO-LUMO energy gap can probably distinguish activators and blockers that have been observed. Genetic Algorithm with Multiple Linear Regression Analysis (GA-MLRA) technique was also applied for the generation of three-descriptor QSAR models for the set of 65 blockers. Additionally to the computational studies, the HOMO-LUMO gap descriptor in each obtained QSAR model has confirmed the crucial role of charge transfer in receptor-ligand interactions. A number of other descriptors such as logP, I(BEG), nNH2, nHDon, nCO have been selected as complementary ones to LUMO and their role in activity alteration has also been discussed.

Aconitum and Delphinium alkaloids "Drug-likeness" descriptors related to toxic mode of action.

Large series of Aconitum and Delphinium alkaloids have been investigated by means of QSAR analysis. Descriptors related to "drug-likeness" of molecules were selected to discriminate between "drugs" and "non-drugs" amongst diterpenoid alkaloids of interest. A usefulness of such approach has been assessed and it proved to give reliable results on whether a particular diterpenoid alkaloid is likely to be either poison or drug. A number of QSAR models with "drug-likeness" descriptors have also been obtained and discussed in terms of their relativity to the mode of toxic action exhibited by the alkaloids. The QSAR models were obtained with r value in the range 0.69-0.94. The q(2) (cross validation of r(2)) values also confirm the statistical significance of our models.

Synthesis, tautomeric states and crystal structure of (Z)-ethyl 2-cyano-2-(3H-quinazoline-4-ylidene) acetate and (Z)-ethyl 2-cyano-2-(2-methyl-3H-quinazoline-4-ylidene) acetate.

The new compounds (Z)-ethyl 2-cyano-2-(3H- and 2-methyl-3H-quinazoline-4-ylidene) acetate (1 and 2, respectively) were synthesized by multi-step reactions. The structures in a solution have been determined by (1)H-NMR spectroscopy and in the crystal form by X-ray analysis. Molecule 1 crystallized in a primitive monoclinic cell, space group capital ER, P2(1/c). The cell dimensions are a=7.970(6) A, b=7.061(2) A, c=20.537(7) A, beta=97.69(5) degrees , V=1145.3(10) A(3). Molecule 2 crystallized in a triclinic cell, space group P-1, the cell dimensions are a=8.196(5) A, b=8.997(6) A, c=9.435(4) A, alpha=74.22(4) degrees, beta=89.75(4) degrees , gamma=74.07(5) degrees , V=641.9(6) A(3). In both compounds the presence of intra-molecular NH---O=C hydrogen bonding between the nitrogen atom in position 3 of the quinazoline ring and a carbonyl group of the ethyl cyanoacetate residue was proven by quantum-chemical, (1)H-NMR and X-ray methods.

A QSAR toxicity study of a series of alkaloids with the lycoctonine skeleton.

A QSAR toxicity analysis has been performed for a series of 19 alkaloids with the lycoctonine skeleton. GA-MLRA (Genetic Algorithm combined with Multiple Linear Regression Analysis) technique was applied for the generation of two types of QSARs: first, models containing exclusively 3D-descriptors and second, models consisting of physicochemical descriptors. As expected, 3D-descriptor QSARs have better statistical fits. Physicochemical-descriptor containing models, that are in a good agreement with the mode of toxic action exerted by the alkaloids studied, have also been identified and discussed. In particular, TPSA (Topological Polar Surface Area) and nC=O (number of -C(O)- fragments) parameters give the best statistically significant mono- and bidescriptor models (when combined with lipophilicity, MlogP) confirming the importance of H-bonding capability of the alkaloids for binding at the receptor site.