Toward a class-independent quantitative structure--activity relationship model for uncouplers of oxidative phosphorylation.

A mechanistically based quantitative structure-activity relationship (QSAR) for the uncoupling activity of weak organic acids has been derived. The analysis of earlier experimental studies suggested that the limiting step in the uncoupling process is the rate with which anions can cross the membrane and that this rate is determined by the height of the energy barrier encountered in the hydrophobic membrane core. We use this mechanistic understanding to develop a predictive model for uncoupling.

Comparative quantitative structure-activity-activity relationships for toxicity to Tetrahymena pyriformis and Pimephales promelas.

An approach for predicting acute aquatic toxicity, in the form of a quantitative structure-activity-activity relationship (QSAAR), is described. This study assessed relative toxic effects to a fish, Pimephales promelas, and a ciliate, Tetrahymena pyriformis, and attempted to form relationships between them. A good agreement between toxic potencies (R2 = 0.

The expanding role of predictive toxicology: an update on the (Q)SAR models for mutagens and carcinogens.

Different regulatory schemes worldwide, and in particular, the preparation for the new REACH (Registration, Evaluation and Authorization of CHemicals) legislation in Europe, increase the reliance on estimation methods for predicting potential chemical hazard. To meet the increased expectations, the availability of valid (Q)SARs becomes a critical issue, especially for endpoints that have complex mechanisms of action, are time-and cost-consuming, and require a large number of animals to test. Here, findings from the survey on (Q)SARs for mutagenicity and carcinogenicity, initiated by the European Chemicals Bureau (ECB) and carried out by the Istituto Superiore di Sanita' are summarized, key aspects are discussed, and a broader view towards future needs and perspectives is given.

Quantitative structure-activity-activity and quantitative structure-activity investigations of human and rodent toxicity.

Acute toxicity in different biological systems, including humans and rodents in vivo, and human and rodent cell lines in vitro, was investigated. The data were taken from the MEIC (Multicentre Evaluation of In Vitro Cytotoxicity) programme. Quantitative structure-activity-activity relationship (QSAAR) models were developed for the in vivo human and rodent toxicity including a combination of toxicity endpoint and structural descriptors as predictor variables.

Comparison of the applicability domain of a quantitative structure-activity relationship for estrogenicity with a large chemical inventory.

The aim of the present study was to illustrate that it is possible and relatively straightforward to compare the domain of applicability of a quantitative structure-activity relationship (QSAR) model in terms of its physicochemical descriptors with a large inventory of chemicals. A training set of 105 chemicals with data for relative estrogenic gene activation, obtained in a recombinant yeast assay, was used to develop the QSAR. A binary classification model for predicting active versus inactive chemicals was developed using classification tree analysis and two descriptors with a clear physicochemical meaning (octanol-water partition coefficient, or log Kow, and the number of hydrogen bond donors, or n(Hdon)).

QSARs for the aquatic toxicity of aromatic aldehydes from Tetrahymena data.

The aim of the study was to develop quantitative structure-activity relationships (QSARs) for a large group of 77 aromatic aldehydes tested for acute toxicity to the ciliate Tetrahymena pyriformis using mechanistically interpretable descriptors. The resulting QSARs revealed that the 1-octanol/water partition coefficient (log K(ow)), is the most important descriptor of aldehyde aquatic toxic potency. The model with log K(ow) was improved by adding electronic descriptor (the maximum acceptor superdelocalizability in a molecule--A(max)) based on calculations with the semi-empirical AM1 model.

Structure-toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, carbonyl-containing, alpha,beta-unsaturated chemicals.

Toxicity data for 82 aliphatic chemicals with an alpha,beta-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic potency [log(IGC50(-1))] for most of these chemicals was in excess of baseline narcosis as quantified by the 1-octanol/water partition coefficient (log K(ow)).

Description of the electronic structure of organic chemicals using semiempirical and ab initio methods for development of toxicological QSARs.

The quality of quantitative structure-activity relationship (QSAR) models depends on the quality of their constitutive elements including the biological activity, statistical procedure applied, and the physicochemical and structural descriptors. The aim of this study was to assess the comparative use of ab initio and semiempirical quantum chemical calculations for the development of toxicological QSARs applied to a large and chemically diverse data set. A heterogeneous collection of 568 organic compounds with 96 h acute toxicity measured to the fish fathead minnow (Pimephales promelas) was utilized.

Assessment and modeling of the toxicity of organic chemicals to Chlorella vulgaris: development of a novel database.

This study reports a database of toxicity values for 91 compounds assessed in a novel, rapid, and economical 15 min algal toxicity test. The toxicity data were measured using the unicellular green alga Chlorella vulgaris in an assay that determined the disappearance of fluorescein diacetate. The chemicals tested covered a wide range of physicochemical properties and mechanisms of action.

QSAR analysis of the toxicity of aromatic compounds to Chlorella vulgaris in a novel short-term assay.

The use of alternative toxicity tests and computational prediction models is widely accepted to fill experimental data gaps and to prioritize chemicals for more expensive and time-consuming assessment. A novel short-term toxicity test using the alga Chlorella vulgaris was utilized in this study to produce acute aquatic toxicity data for 65 aromatic compounds. The compounds tested included phenols, anilines, nitrobenzenes, benzaldehydes and other poly-substituted benzenes.

Comparative assessment of methods to develop QSARs for the prediction of the toxicity of phenols to Tetrahymena pyriformis.

Quantitative structure-activity relationships (QSARs) for the toxicity of 200 phenols to the ciliated protozoan Tetrahymena pyriformis, and the validation of the QSARs using a test set of a further 50 compounds, are reported. The phenols are structurally heterogeneous and represent a variety of mechanisms of toxic action including polar narcosis, weak acid respiratory uncoupling, electrophilicity, and those compounds capable of being metabolised or oxidised to quinones. For each compound, a total of 108 physico-chemical descriptors have been calculated.

Structure-toxicity relationships for aliphatic chemicals evaluated with Tetrahymena pyriformis.

Quantitative structure-activity relationships were developed for the toxicity data of 500 aliphatic chemicals tested in the two-day Tetrahymena pyriformis population growth impairment assay. These chemicals represented a number of structural classes spanning a variety of mechanisms of toxic action including narcoses and electrophilic mechanisms. A series of quantitative structure-toxicity models correlating toxic potency [log(IGC(50)(-1))] with a limited number of mechanistically interpretable descriptors were developed for toxicological domains within the data set.

Structure-based classification of antibacterial activity.

The aim of this study was to develop a simple quantitative structure-activity relationship (QSAR) for the classification and prediction of antibacterial activity, so as to enable in silico screening. To this end a database of 661 compounds, classified according to whether they had antibacterial activity, and for which a total of 167 physicochemical and structural descriptors were calculated, was analyzed. To identify descriptors that allowed separation of the two classes (i.