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      4D-fingerprint categorical QSAR models for skin sensitization based on the classification of local lymph node assay measures.

      Chemical Research in Toxicology
      Animals, Guinea Pigs, Least-Squares Analysis, Logistic Models, Lymph Nodes, drug effects, Quantitative Structure-Activity Relationship, Skin, Toxicity Tests

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          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.

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          Author and article information

          Journal
          17226934
          2553001
          10.1021/tx6002535

          Chemistry
          Animals,Guinea Pigs,Least-Squares Analysis,Logistic Models,Lymph Nodes,drug effects,Quantitative Structure-Activity Relationship,Skin,Toxicity Tests

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