title: 4D-fingerprint categorical QSAR models for skin sensitization based on the classification of local lymph node assay measures.
abstract: Currently, the only validated methods to identify skin sensitization effects are in vivo models, such as the local lymph node assay (LLNA) and guinea pig studies. There is a tremendous need, in particular due to novel legislation, to develop animal alternatives, for eaxample, quantitative structure-activity relationship (QSAR) models. Here, QSAR models for skin sensitization using LLNA data have been constructed. The descriptors used to generate these models are derived from the 4D-molecular similarity paradigm and are referred to as universal 4D-fingerprints. A training set of 132 structurally diverse compounds and a test set of 15 structurally diverse compounds were used in this study. The statistical methodologies used to build the models are logistic regression (LR) and partial least-square coupled logistic regression (PLS-LR), which prove to be effective tools for studying skin sensitization measures expressed in the two categorical terms of sensitizer and non-sensitizer. QSAR models with low values of the Hosmer-Lemeshow goodness-of-fit statistic, X(2)HL, are significant and predictive. For the training set, the cross-validated prediction accuracy of the logistic regression models ranges from 77.3% to 78.0%, whereas that of the PLS-logistic regression models ranges from 87.1% to 89.4%. For the test set, the prediction accuracy of logistic regression models ranges from 80.0% to 86.7%, whereas that of the PLS-logistic regression models ranges from 73.3% to 80.0%. The QSAR models are made up of 4D-fingerprints related to aromatic atoms, hydrogen bond acceptors, and negatively partially charged atoms.
authors.affiliation: Laboratory of Molecular Modeling and Design (MC 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Yufeng J
authors.initials: YJ
authors.lastname: Tseng
authors.forename: Dahua
authors.initials: D
authors.lastname: Pan
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Liu
authors.forename: Petra S
authors.initials: PS
authors.lastname: Kern
authors.forename: G Frank
authors.initials: GF
authors.lastname: Gerberick
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Hopfinger
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D016018:Least-Squares Analysis; D016015:Logistic Models; D008198:Lymph Nodes / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000187:drug effects*; D018675:Toxicity Tests