RESUMEN
Computer simulation of xenobiotic metabolism and degradation is usually performed proceeding from a set of expert-developed rules modelling the actual enzyme-driven chemical reactions. With the accumulation of extensive metabolic pathway data, the analysis required to derive such chemical reaction patterns has become more objective, but also more convoluted and demanding. Herein we report on our computer-based approach for the analysis of metabolic maps, leading to the construction of reaction rules statistically suitable for simulation purposes. It is based on the set of so-called bare transformations which encompass all unique reaction patterns as obtained by a heuristically enhanced maximum common subgraph algorithm. The bare transformations guarantee that no existing metabolite is missed in simulation at the expense of an enormous amount of false positive predictions. They are rendered more selective by correlating the generated true and false positives to the locations of typical chemical functional groups in the potential reactants. The approach and its results are illustrated for a metabolic map collection of 15 cycloalkanes.
Asunto(s)
Cicloparafinas/metabolismo , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/toxicidad , Modelos Biológicos , Animales , Bacterias/metabolismo , Biotransformación , Simulación por Computador , Cicloparafinas/toxicidad , Humanos , Redes y Vías Metabólicas , Modelos Estadísticos , Relación Estructura-Actividad CuantitativaRESUMEN
The unprecedented pollution of the environment by xenobiotic compounds has provoked the need to understand the biodegradation potential of chemicals. Mechanistic understanding of microbial degradation is a premise for adequate modelling of the environmental fate of chemicals. The aim of the present paper is to describe abiotic and biotic models implemented in CATALOGIC software. A brief overview of the specificities of abiotic and microbial degradation is provided followed by detailed descriptions of models built in our laboratory during the last decade. These are principally new models based on unique mathematical formalism already described in the first paper of this series, which accounts more adequately than currently available approaches the multipathway metabolic logic in prokaryotes. Based on simulated pathways of degradation, the models are able to predict quantities of transformation products, biological oxygen demand (BOD), carbon dioxide (CO(2)) production, and primary and ultimate half-lives. Interpretation of the applicability domain of models is also discussed.
Asunto(s)
Biotransformación , Simulación por Computador , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/toxicidad , Xenobióticos/metabolismo , Xenobióticos/toxicidad , Análisis de la Demanda Biológica de Oxígeno , Dióxido de Carbono/metabolismo , Contaminantes Ambientales/química , Redes y Vías Metabólicas , Medición de Riesgo/métodos , Programas Informáticos , Xenobióticos/químicaRESUMEN
The awareness of air, soil and water pollution has driven the search for better methods for the assessment of the environmental fate of industrial chemicals. This paper is focused on the simulation of formation and transformation of metabolites in soil. The key challenges in the development of a simulator for predicting metabolic fate of chemicals in soil are the complexity of the soil compartment and incompleteness of metabolic information. Based on the collected data for metabolic fate of 183 chemicals a set of soil specific transformations were defined and used to develop a simulator for metabolism in soil. The analysis of outliers showed that the low predictability for some chemicals is due to: 1) incomplete documented metabolic pathways with missing intermediates and/or 2) reactions of condensation that are not simulated in the current version of the model. Hence, further improvement of the model requires expanding the metabolism database and further refinement of the logic of metabolic transformations used in the simulator.
Asunto(s)
Monitoreo del Ambiente/métodos , Modelos Químicos , Contaminantes del Suelo/metabolismo , Biodegradación Ambiental , Contaminación Ambiental/estadística & datos numéricos , Predicción , Microbiología del Suelo , Contaminantes del Suelo/químicaRESUMEN
Biodegradation plays a key role in the environmental risk assessment of organic chemicals. The need to assess biodegradability of a chemical for regulatory purposes supports the development of a model for predicting the extent of biodegradation at different time frames, in particular the extent of ultimate biodegradation within a '10 day window' criterion as well as estimating biodegradation half-lives. Conceptually this implies expressing the rate of catabolic transformations as a function of time. An attempt to correlate the kinetics of biodegradation with molecular structure of chemicals is presented. A simplified biodegradation kinetic model was formulated by combining the probabilistic approach of the original formulation of the CATABOL model with the assumption of first order kinetics of catabolic transformations. Nonlinear regression analysis was used to fit the model parameters to OECD 301F biodegradation kinetic data for a set of 208 chemicals. The new model allows the prediction of biodegradation multi-pathways, primary and ultimate half-lives and simulation of related kinetic biodegradation parameters such as biological oxygen demand (BOD), carbon dioxide production, and the nature and amount of metabolites as a function of time. The model may also be used for evaluating the OECD ready biodegradability potential of a chemical within the '10-day window' criterion.
Asunto(s)
Bacterias/metabolismo , Biodegradación Ambiental , Modelos Biológicos , Modelos Químicos , Dióxido de Carbono/metabolismo , Simulación por Computador , Semivida , Cinética , Oxígeno/metabolismo , Análisis de Regresión , Relación Estructura-ActividadRESUMEN
A multi-dimensional formulation of the COmmon REactivity PAttern (COREPA) modeling approach has been used to investigate chemical binding to the human estrogen receptor (hER). A training set of 645 chemicals included 497 steroid and environmental chemicals (database of the Chemical Evaluation and Research Institute, Japan - CERI) and 148 chemicals to further explore hER-structure interactions (selected J. Katzenellenbogen references). Upgrades of modeling approaches were introduced for multivariate COREPA analysis, optimal conformational generation and description of the local hydrophobicity of chemicals. Analysis of reactivity patterns based on the distance between nucleophilic sites resulted in identification of distinct interaction types: a steroid-like A-B type described by frontier orbital energies and distance between nucleophilic sites with specific charge requirements; an A-C type where local hydrophobic effects are combined with electronic interactions to modulate binding; and mixed A-B-C (AD) type. Chemicals were grouped by type, then COREPA models were developed for within specific relative binding affinity ranges of >10%, 10 > RBA > or = 0.1%, and 0.1 > RBA > 0.0%. The derived models for each interaction type and affinity range combined specific prefiltering requirements (interatomic distances) and a COREPA classification node using no more than 2 discriminating parameters. The interaction types are becoming less distinct in the lowest activity range for each chemicals of each type; here, the modeling was performed within chemical classes (phenols, phthalates, etc.). The ultimate model was organized as a battery of local models associated to interaction type and mechanism.