The definition of the applicability domain relevant to skin sensitization for the aromatic nucleophilic substitution mechanism.
This study outlines how a glutathione reactivity assay (so-called in chemico data) can be used to define the applicability domain for the nucleophilic aromatic substitution (S(N)Ar) reaction for benzenes. This reaction is one of the six mechanistic domains that have been shown to be important in toxicological endpoints in which the ability to bind covalently to a protein is a key molecular initiating event. This study has analysed the experimental data, allowing a clear and interpretable structure-activity relationship to be developed for the S(N)Ar domain. The applicability domain has resulted in a series of structural alerts. The definition of the applicability domain for the S(N)Ar reaction and the resulting structural alerts are likely to be beneficial in the development of computational tools for category formation and read-across. The study concludes with how this information can be used in the development of adverse outcome pathways.
School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, England.
S J
SJ
Enoch
T W
TW
Schultz
M T D
MT
Cronin
D001555:Benzene Derivatives / Q000737:chemistry* / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006241:Haptens / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D012867:Skin / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D006241:Haptens; D005978:Glutathione