QSAR prioritization of chemical inventories for endocrine disruptor
testing
P. Schmieder, O. Mekenyan, S. Bradbury, and G. Veith
U.S. Environmental Protection Agency, Office of Research
and Development, National Health and Environmental Effects Research
Laboratory, Mid- Continent Ecology Division, 6201 Congdon Blvd., Duluth,
MN 55804, USA;
Laboratory of Mathematical Chemistry, University Prof. As. Zlatarov
, 8010 Bourgas, Bulgaria;
U.S. Environmental Protection Agency, Office of Pesticide Programs,
Environmental Fate and Effects Division, Washington, DC 20460, USA
Abstract: Binding affinity between chemicals and the estrogen
receptor (ER) serves as an indicator of the potential to cause endocrine
disruption through this receptor-mediated endocrine pathway. Estimating
ER-binding affinity is, therefore, one strategic approach to reducing
the costs of screening chemicals for potential risks of endocrine disruption.
While measuring ER binding with in vitro assays may be the first choice
in prioritizing chemicals for additional in vitro or in vivo estrogenicity
testing, the time and costs associated with screening thousands of chemicals
is prohibitive. Recent advances in 3D modeling of the reactivity of
flexible structures make in silico methods for estimating ER binding
possible. One technique, the common reactivity pattern (COREPA) approach,
was applied to development of reactivity patterns for ER relative binding
affinity based on global nucleophilicity, interatomic distances between
nucleophilic sites, and local electron donor capability of the nucleophilic
sites. The reactivity patterns provided descriptor profiles for order-of-magnitude
RBA ranges of training set chemicals. An exploratory expert system was
subsequently developed to predict RBA and rank chemicals with respect
to potential estrogenicity. A strategy is presented for extending initial
exploratory 3D QSAR models beyond current training sets to increase
applicability to more diverse structures in large chemical inventories.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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