4D-fingerprint categorical QSAR models for skin sensitization based on the classification of local lymph node assay measures.
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.
Li
Yi
Y
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.
Tseng
Yufeng J
YJ
Pan
Dahua
D
Liu
Jianzhong
J
Kern
Petra S
PS
Gerberick
G Frank
GF
Hopfinger
Anton J
AJ
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