title: Modeling skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol compounds with quantum mechanistic properties.
abstract: BACKGROUND
  Advanced structure-activity relationship (SAR) modeling can be used as an alternative tool for identification of skin sensitizers and in improvement of the medical diagnosis and more effective practical measures to reduce the causative chemical exposures. It can also circumvent ethical concern of using animals in toxicological tests, and reduce time and cost. Compounds with aniline or phenol moieties represent two large classes of frequently skin sensitizing chemicals but exhibiting very variable, and difficult to predict, potency. The mechanisms of action are not well-understood.
  
  
  METHODS
  A group of mechanistically hard-to-be-classified aniline and phenol chemicals were collected. An in silico model was established by statistical analysis of quantum descriptors for the determination of the relationship between their chemical structures and skin sensitization potential. The sensitization mechanisms were investigated based on the features of the established model. Then the model was utilized to analyze a subset of FDA approved drugs containing aniline and/or phenol groups for prediction of their skin sensitization potential.
  
  
  CONCLUSIONS
  A linear discriminant model using the energy of the highest occupied molecular orbital (ϵHOMO) as the descriptor yielded high prediction accuracy. The contribution of ϵHOMO as a major determinant may suggest that autoxidation or free radical binding could be involved. The model was further applied to predict allergic potential of a subset of FDA approved drugs containing aniline and/or phenol moiety. The predictions imply that similar mechanisms (autoxidation or free radical binding) may also play a role in the skin sensitization caused by these drugs.
  
  
  CONCLUSIONS
  An accurate and simple quantum mechanistic model has been developed to predict the skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol chemicals. The model could be useful for the skin sensitization potential predictions of a subset of FDA approved drugs.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Lirong
authors.initials: L
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center, of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, Pittsburgh, PA 15261, USA. xix15@pitt.edu.
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
mesh_terms: D000814:Aniline Compounds / Q000633:toxicity*; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D006801:Humans; D008954:Models, Biological; D010636:Phenols / Q000633:toxicity*; D011789:Quantum Theory
chemical_list: D000814:Aniline Compounds; D010636:Phenols