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Density Functional Theory Transition-State Modeling for the Prediction of Ames Mutagenicity in 1,4 Michael Acceptors
journal contribution
posted on 2019-12-10, 18:45 authored by Piers
A. Townsend, Matthew N. GraysonAssessing the safety of new chemicals, without introducing
the
need for animal testing, is a task of great importance. The Ames test,
a widely used bioassay to assess mutagenicity, can be an expensive,
wasteful process with animal-derived reagents. Existing in silico
methods for the prediction of Ames test results are traditionally
based on chemical category formation and can lead to false positive
predictions. Category formation also neglects the intrinsic chemistry
associated with DNA reactivity. Activation energies and HOMO/LUMO
energies for thirty 1,4 Michael acceptors were calculated using a
model nucleobase and were further used to predict the Ames test result
of these compounds. The proposed model builds upon existing work and
examines the fundamental toxicant–target interactions using
density functional theory transition-state modeling. The results show
that Michael acceptors with activation energies <20.7 kcal/mol
and LUMO energies < −1.85 eV are likely to act as direct
mutagens upon exposure to DNA.
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predictiontheory transition-state modelinganimal-derived reagentsHOMOresults showLUMO energiesAmes test resultsCategory formationanimal testingmodel nucleobaseAmes testDNA reactivityAmes test resultAmes MutagenicityMichael acceptorssilico methodsActivation energieschemical category formationDensity Functional Theory Transition-State Modeling
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