Citation:

Bailey, G W. AND T. M. Jenkins. CHARACTERIZING THE CONFORMATIONAL AND ELECTRONIC PROPERTIES OF CONAZOLE FUNGICIDES. Presented at Soil Science Society of America Annual Meeting, Seattle, WA, October 31-November 4, 2004.

Impact/Purpose:

This task is divided into four major research areas: (1) Development of computational tools and databases for screening-level modeling of the environmental fate of organic chemicals; (2) Metabolism of xenobiotics: Enhancing the development of a metabolic simulator; (3) Metabonomics: The use of advanced analytical tools to identify toxicity pathways; and (4) Software infrastructure to support development and application of transformation/metabolic simulators.

For many chemicals, multiple transformation/metabolic pathways can exist. Consequently, transformation/metabolic simulators must utilize transformation rate data for prioritization of competing pathways. The prioritization process thus requires the integration of reliable rate data. When this data is absent, it is necessary to generate a database with metabolic and transformation rate constants based on: (1) experimentally measured values, including those requiring the use of advanced analytical techniques for measuring metabolic rate constants in vivo and in vitro; (2) rate constants derived from SPARC and mechanistic-based QSAR models; and (3) data mined from the literature and Program Office CBI. A long-term goal of this project is to build this database. This information will be used to enhance the predictive capabilities of the transformation/metabolic simulators. As indicated previously, exposure genomics, which provide early signs of chemical exposure based on changes in gene expression, will be used to guide chemical fate and metabolism studies. The incorporation of exposure genomics into fate studies will provide information concerning (1) the minimal concentrations at which biological events occur; and (2) the identification of biologically relevant chemicals(s) in mixtures.

The capability of categorizing chemicals and their metabolites based on toxicity pathway is imperative to the success of the CompTox Research Program. Metabonomics, which is the multi-parametric measurement of metabolites in living systems due to physiological stimuli and/or genetic modification, provides such a capability. The application of metabonomics to toxicity testing involves the elucidation of changes in metabolic patterns associated with chemical toxicity based on the measurement of component profiles in biofluids, and enables the generation of spectral profiles for a wide range of endogenous metabolites. Metabolic profiles can provide a measure of the real outcome of potential changes as the result of xenobiotic exposure.

Description:

Conazole fungicides have important environmental and human health considerations including chemical reactivity and transformation pathways. The electronic and conformational properties of an organic molecule determines in conjunction with solvent properties, its chemical reactivity and transformation pathways. Mapping of properties on a molecular surface provides a 3-dimensional graphic representation of each property superimposed on the chemical structure of the molecule. Surface properties - partial atomic charges, lipophilic potential, electrostatic potential, hydrogen bonding sites, hydrogen acceptor/acceptor donor density, local curvature, and cavity depth - were computed and mapped onto the chemical structure of a 1,2,4-triazole fungicide - bromuconazole - using MOLCAD PM3. Graphical representation of each property at various spatial orientations will demonstrate the utility of the approach to gain insight into molecular properties of conazole fungicides and other small organic molecules.

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