Avoidance of the Ames test liability for Aryl-amines via computation.
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Mccarren, Patrick, Bebernitz, Gregory, Gedeck, Peter, Glowienke, Susanne, Grondine, Melissa, Kirman, Louise, Klickstein, Jacob, Schuster, Herbert and Whitehead, Lewis (2011) Avoidance of the Ames test liability for Aryl-amines via computation. Bioorganic and Medicinal Chemistry, 19 (10). pp. 3173-3182. ISSN 0968-0896
Abstract
Aryl-amines are commonly used synthons in modern drug discovery, however a minority of these chemical templates have the potential to cause toxicity through mutagenicity. The toxicity mostly arises through a series of metabolic steps leading to a reactive electrophilic nitrenium cation intermediate that reacts with DNA nucleotides causing mutation. Highly detailed in-silico calculations of the energetics of chemical reactions involved in the metabolic formation of nitrenium cations have been performed. This allowed a critical assessment of the accuracy and reliability of using a theoretical formation energy of the DNA-reactive nitrenium intermediate to correlate with the Ames test response. This study contains the largest data set reported to date, and presents the in-silico calculations versus the in-vitro Ames response data in the form of beanplots commonly used in statistical analysis. A comparison of this quantum mechanical approach to QSAR and knowledge-based methods is also reported, as well as the calculated formation energies of nitrenium ions for thousands of commercially available aryl-amines generated as a watch-list for medicinal chemists in their synthetic optimization strategies.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | Aryl-amines, Toxicity prediction, Nitrenium, Ames, Density Functional Theory |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/4764 |