Abstract
The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modeling of the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly with DNA and form a covalent bond. Such approaches sometimes predict false positives, as not all Michael acceptors are found to be Ames-positive. The formation of such covalent bonds can be explored computationally using density functional theory transition state modeling. We have applied this approach to mutagenicity, allowing us to calculate the activation energy required for α,β-unsaturated carbonyls to react with a model system for the guanine nucleobase of DNA. These calculations have allowed us to identify that chemical compounds with activation energies greater than or equal to 25.7 kcal/mol are not able to bind directly to DNA. This allows us to reduce the false positive rate for computationally predicted mutagenicity assays. This methodology can be used to investigate other covalent-bond-forming reactions that can lead to toxicological outcomes and learn more about experimental results.
| Language | English |
|---|---|
| Pages | 1266-1271 |
| Number of pages | 6 |
| Journal | Journal of Chemical Information and Modeling |
| Volume | 58 |
| Issue number | 6 |
| Early online date | 30 May 2018 |
| DOIs | |
| Status | Published - 25 Jun 2018 |
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ASJC Scopus subject areas
- Chemistry(all)
- Chemical Engineering(all)
- Computer Science Applications
- Library and Information Sciences
Cite this
Using Transition State Modeling to Predict Mutagenicity for Michael Acceptors. / Allen, Timothy E.H.; Grayson, Matthew N.; Goodman, Jonathan M.; Gutsell, Steve; Russell, Paul J.
In: Journal of Chemical Information and Modeling, Vol. 58, No. 6, 25.06.2018, p. 1266-1271.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Using Transition State Modeling to Predict Mutagenicity for Michael Acceptors
AU - Allen, Timothy E.H.
AU - Grayson, Matthew N.
AU - Goodman, Jonathan M.
AU - Gutsell, Steve
AU - Russell, Paul J.
PY - 2018/6/25
Y1 - 2018/6/25
N2 - The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modeling of the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly with DNA and form a covalent bond. Such approaches sometimes predict false positives, as not all Michael acceptors are found to be Ames-positive. The formation of such covalent bonds can be explored computationally using density functional theory transition state modeling. We have applied this approach to mutagenicity, allowing us to calculate the activation energy required for α,β-unsaturated carbonyls to react with a model system for the guanine nucleobase of DNA. These calculations have allowed us to identify that chemical compounds with activation energies greater than or equal to 25.7 kcal/mol are not able to bind directly to DNA. This allows us to reduce the false positive rate for computationally predicted mutagenicity assays. This methodology can be used to investigate other covalent-bond-forming reactions that can lead to toxicological outcomes and learn more about experimental results.
AB - The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modeling of the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly with DNA and form a covalent bond. Such approaches sometimes predict false positives, as not all Michael acceptors are found to be Ames-positive. The formation of such covalent bonds can be explored computationally using density functional theory transition state modeling. We have applied this approach to mutagenicity, allowing us to calculate the activation energy required for α,β-unsaturated carbonyls to react with a model system for the guanine nucleobase of DNA. These calculations have allowed us to identify that chemical compounds with activation energies greater than or equal to 25.7 kcal/mol are not able to bind directly to DNA. This allows us to reduce the false positive rate for computationally predicted mutagenicity assays. This methodology can be used to investigate other covalent-bond-forming reactions that can lead to toxicological outcomes and learn more about experimental results.
UR - http://www.scopus.com/inward/record.url?scp=85048022296&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.8b00130
DO - 10.1021/acs.jcim.8b00130
M3 - Article
VL - 58
SP - 1266
EP - 1271
JO - Journal of Chemical Information and Modeling
T2 - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
SN - 1549-9596
IS - 6
ER -