Density Functional Theory Transition-State Modeling for the Prediction of Ames Mutagenicity in 1,4 Michael Acceptors

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Abstract

Assessing 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.

Original languageEnglish
JournalJournal of Chemical Information and Modeling
Early online date27 Nov 2019
DOIs
Publication statusE-pub ahead of print - 27 Nov 2019

Cite this

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title = "Density Functional Theory Transition-State Modeling for the Prediction of Ames Mutagenicity in 1,4 Michael Acceptors",
abstract = "Assessing 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.",
author = "Townsend, {Piers A} and Grayson, {Matthew N}",
year = "2019",
month = "11",
day = "27",
doi = "10.1021/acs.jcim.9b00966",
language = "English",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",

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T1 - Density Functional Theory Transition-State Modeling for the Prediction of Ames Mutagenicity in 1,4 Michael Acceptors

AU - Townsend, Piers A

AU - Grayson, Matthew N

PY - 2019/11/27

Y1 - 2019/11/27

N2 - Assessing 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.

AB - Assessing 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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