Experimental verification, and domain definition, of structural alerts for protein binding: epoxides, lactones, nitroso, nitros, aldehydes and ketones

• Published in: SAR and QSAR in environmental research 2013-09, Vol.24 (9), p.695-709
• Main Authors: Nelms, M.D., Cronin, M.T.D., Schultz, T.W., Enoch, S.J.
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Aldehydes - metabolism; Aldehydes - toxicity; applicability domain; category formation; electrophilic reaction chemistry; Epoxy Compounds - chemistry; Epoxy Compounds - metabolism; Epoxy Compounds - toxicity; Glutathione - metabolism; in chemico; Ketones - chemistry; Ketones - metabolism; Ketones - toxicity; Lactones - chemistry; Lactones - metabolism; Lactones - toxicity; Nitrosamines - chemistry; Nitrosamines - metabolism; Nitrosamines - toxicity; Nitroso Compounds - chemistry; Nitroso Compounds - metabolism; Nitroso Compounds - toxicity; OECD QSAR Toolbox; Organic Chemicals - chemistry; Organic Chemicals - metabolism; Organic Chemicals - toxicity; Protein Binding; Protozoan Proteins - metabolism; structural alerts; Structure-Activity Relationship; Tetrahymena pyriformis - drug effects; Tetrahymena pyriformis - growth & development; Toxicology - methods
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2013.792874

This study outlines how a combination of in chemico and Tetrahymena pyriformis data can be used to define the applicability domain of selected structural alerts within the profilers of the OECD QSAR Toolbox. Thirty-three chemicals were profiled using the OECD and OASIS profilers, enabling the applicability domain of six structural alerts to be defined, the alerts being: epoxides, lactones, nitrosos, nitros, aldehydes and ketones. Analysis of the experimental data showed the applicability domains for the epoxide, nitroso, aldehyde and ketone structural alerts to be well defined. In contrast, the data showed the applicability domains for the lactone and nitro structural alerts needed modifying. The accurate definition of the applicability domain for structural alerts within in silico profilers is important due to their use in the chemical category in predictive and regulatory toxicology. This study highlights the importance of utilizing multiple profilers in category formation.