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PHYSICOCHEMICAL PROPERTY CALCULATIONS
CARREIRA, L. A., T. S. WHITESIDE, A. N. SARAVANARAJ, AND S. H. HILAL. PHYSICOCHEMICAL PROPERTY CALCULATIONS. Presented at American Chemical Society Meeting, San Francisco, CA, September 10 - 14, 2006.
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.
Computer models have been developed to estimate a wide range of physical-chemical properties from molecular structure. The SPARC modeling system approaches calculations as site specific reactions (pKa, hydrolysis, hydration) and `whole molecule' properties (vapor pressure, boiling point, molecular volume, diffusion coefficient, electron affinity, refractive index, Henry's constant, solubility, activity coefficient, liquid/liquid portioning). The system consists of a toolbox of base models whose parameters are shared across both site specific and whole molecule properties. The power of the technique is its ability to couple whole molecule and site specific chemistry to calculate new properties. For example water pKa and properties models are coupled to calculate the gas phase pKa and the pKa in any solvent or mixed solvent. pKa and property models are coupled to calculate tautomeric equilibrium constants in any solvent. pKa, hydrolysis and property models are coupled to calculate complex macro pKa's where ionization, hydrolysis and tautomerization may couple to yield very complex apparent pKa's. pKa and partition coefficient are coupled to calculate logD distributions as a function of pH. Several examples of complex modeling will be presented.