High-throughput in-silico prediction of ionization equilibria for pharmacokinetic modeling.

Chemical ionization plays an important role in many aspects of pharmacokinetic (PK) processes such as protein binding, tissue partitioning, and apparent volume of distribution at steady state (Vd). Here, estimates of ionization equilibrium constants (i.e.

Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets.

Understanding the potential health risks posed by environmental chemicals is a significant challenge elevated by the large number of diverse chemicals with generally uncharacterized exposures, mechanisms, and toxicities. The present study is a performance evaluation and critical analysis of assay results for an array of 292 high-throughput cell-free assays aimed at preliminary toxicity evaluation of 320 environmental chemicals in EPA's ToxCast™ project (Phase I). The chemicals (309 unique, 11 replicates) were mainly precursors or the active agent of commercial pesticides, for which a wealth of in vivo toxicity data is available.

Molecular modeling for screening environmental chemicals for estrogenicity: use of the toxicant-target approach.

There is a paucity of relevant experimental information available for the evaluation of the potential health and environmental effects of many man made chemicals. Knowledge of the potential pathways for activity provides a rational basis for the extrapolations inherent in the preliminary evaluation of risk and the establishment of priorities for obtaining missing data for environmental chemicals. The differential step in many mechanisms of toxicity may be generalized as the interaction between a small molecule (a potential toxicant) and one or more macromolecular targets.

Computational molecular modeling for evaluating the toxicity of environmental chemicals: prioritizing bioassay requirements.

Background: The human health risk from exposure to environmental chemicals often must be evaluated when relevant elements of the preferred data are unavailable. Therefore, strategies are needed that can predict this information and prioritize the outstanding data requirements for the risk evaluation. Many modes of molecular toxicity require the chemical or one of its biotransformation products to interact with specific biologic macromolecules (i.

Benzo[a]pyrene and benz[c]phenanthrene: the effect of structure on the binding of water molecules to the diol epoxides.

The interactions with water of the diol epoxides (DEs) of both a planar and a nonplanar PAH have been examined using molecular dynamics. To determine probable water locations around the DE for later use in the study of DE protonation, molecular dynamics simulations using the OPLS force field were carried out on diol epoxides surrounded by a 22 A box of explicit water molecules. Results for 30 ps simulations indicate that 10-60% of the time, depending strongly on the conformation and type of the DE, there is a water molecule forming a hydrogen bond with the epoxide oxygen.