| Computational Molecular Modeling for Evaluating the Toxicity of Environmental Chemicals: Prioritizing Bioassay Requirements James R. Rabinowitz, Michael-Rock Goldsmith,
Stephen B. Little, and Melissa A. Pasquinelli National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA Abstract
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.e., proteins and DNA) . Molecular modeling approaches may be adapted to study the interactions of environmental chemicals with biomolecular targets. Objective: In this commentary we provide an overview of the challenges that arise from applying molecular modeling tools developed and commonly used for pharmaceutical discovery to the problem of predicting the potential toxicities of environmental chemicals. Discussion: The use of molecular modeling tools to predict the unintended health and environmental consequences of environmental chemicals differs strategically from the use of the same tools in the pharmaceutical discovery process in terms of the goals and potential applications. It also requires consideration of the greater diversity of chemical space and binding affinity domains than is covered by pharmaceuticals. Conclusion: Molecular modeling methods offer one of several complementary approaches to evaluate the risk to human health and the environment as a result of exposure to environmental chemicals. These tools can streamline the hazard assessment process by simulating possible modes of action and providing virtual screening tools that can help prioritize bioassay requirements. Tailoring these strategies to the particular challenges presented by environmental chemical interactions make them even more effective. Key words: computational toxicology, docking, enrichment, false negatives, high-throughput screening, molecular modeling, prioritizing bioassays, virtual screening. Environ Health Perspect 116:573–577 (2008) . doi:10.1289/ehp.11077 available via http://dx.doi.org/ [Online 1 February 2008]
Address correspondence to M.A. Pasquinelli, North Carolina State University, Fiber and Polymer Science/Department of TECS, Campus Box 8301, 2401 Research Dr., Raleigh, NC 27695 USA. Telephone: (919) 515-9426. Fax: (919) 515-6532. E-mail: Melissa_Pasquinelli@ncsu.edu During a portion of this work, M-R.G. was supported by National Health and Environmental Effects Research Laboratory-Department of Environmental Sciences and Engineering Training Agreement EPA CT829471. This work was reviewed by the U.S. Environmental Protection Agency and approved for publication but does not necessarily reflect official agency policy. The authors declare they have no competing financial interests. Received 16 November 2007 ; accepted 1 February 2008.
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