Identification of the structural requirements for mutagencitiy, by incorporating molecular flexibility and metabolic activation of chemicals. II. General Ames mutagenicity model

Abstract

The tissue metabolic simulator (TIMES) modeling approach is a hybrid expert system that couples a metabolic simulator together with structure toxicity rules, underpinned by structural alerts, to predict interaction of chemicals or their metabolites with target macromolecules. Some of the structural alerts representing the reactivity pattern-causing effect could interact directly with the target whereas others necessitated a combination with two- or three-dimensional quantitative structure-activity relationship models describing the firing of the alerts from the rest of the molecules. Recently, TIMES has been used to model bacterial mutagenicity [Mekenyan, O., Dimitrov, S., Serafimova, R., Thompson, E., Kotov, S., Dimitrova, N., and Walker, J. (2004) Identification of the structural requirements for mutagenicity by incorporating molecular flexibility and metabolic activation of chemicals I: TA100 model. Chem. Res. Toxicol. 17 (6), 753-766]. The original model was derived for a single tester strain, Salmonella typhimurium (TA100), using the Ames test by the National Toxicology Program (NTP). The model correctly identified 82% of the primary acting mutagens, 94% of the nonmutagens, and 77% of the metabolically activated chemicals in a training set. The identified high correlation between activities across different strains changed the initial strategic direction to look at the other strains in the next modeling developments. In this respect, the focus of the present work was to build a general mutagenicity model predicting mutagenicity with respect to any of the Ames tester strains. The use of all reactivity alerts in the model was justified by their interaction mechanisms with DNA, found in the literature. The alerts identified for the current model were analyzed by comparison with other established alerts derived from human experts. In the new model, the original NTP training set with 1341 structures was expanded by 1626 proprietary chemicals provided by BASF AG. Eventually, the training set consisted of 435 chemicals, which are mutagenic as parents, 397 chemicals that are mutagenic after S9 metabolic activation, and 2012 nonmutagenic chemicals. The general mutagenicity model was found to have 82% sensitivity, 89% specificity, and 88% concordance for training set chemicals. The model applicability domain was introduced accounting for similarity (structural, mechanistic, etc.) between predicted chemicals and training set chemicals for which the model performs correctly.