Using Transition State Modeling To Predict Mutagenicity for Michael Acceptors

• Published in: Journal of chemical information and modeling Vol. 58; no. 6; pp. 1266 - 1271
• Main Authors: Allen, Timothy E. H, Grayson, Matthew N, Goodman, Jonathan M, Gutsell, Steve, Russell, Paul J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25.06.2018
• Subjects: Activation energy; Assaying; Carbonyls; Chemical bonds; Chemical compounds; Covalence; Covalent bonds; Density functional theory; Deoxyribonucleic acid; DNA; In vitro methods and tests; Mathematical models; Mutagenesis; Mutagenicity; Organic chemistry; Phase transitions
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.8b00130

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.