HILAL, S. H., A. N. SARAVANARAJ, T. WHITESIDE, AND L. A. CARREIRA. CALCULATING PHYSICAL PROPERTIES OF ORGANIC COMPOUNDS FOR ENVIRONMENTAL MODELING FROM MOLECULAR STRUCTURE. Journal of Computer-Aided Molecular Design. Springer, New York, NY, 21(12):693-708, (2007).
Mathematical models for predicting the transport and fate of pollutants in the environment require reactivity parameter values-- that is value of the physical and chemical constants that govern reactivity. Although empirical structure activity relationships have been developed that allow estimation of some constants, such relationships are generally valid only within limited families of chemicals. The computer program, SPARC, uses computational algorithms based on fundamental chemical structure theory to estimate a large number of chemical reactivity parameters and physical properties for a wide range of organic molecules strictly from molecular structure. Resonance models were developed and calibrated using measured light absorption spectra, whereas electrostatic interaction models were developed using measured ionization pKas in water. Solvation models (i.e., dispersion, induction, H-bonding, etc.) have been developed using various measured physical properties data. At the present time, SPARC's physical property models can predict vapor pressure and heat of vaporization (as a function of temperature), boiling point (as a function of pressure), diffusion coefficient (as a function of pressure and temperature), activity coefficient, solubility, partition coefficient and chromatographic retention time as a function of solvent and temperature. This prediction capability crosses chemical family boundaries to cover a broad range of organic compounds.
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.