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Polar narcosis: Designing a suitable training set for QSAR studies

  • Eñaut Urrestarazu Ramos
  • Wouter H. J. Vaes
  • Henk J. M. Verhaar
  • Joop L. M. Hermens
Series: QSARs in Predictive Environmental Toxicology

Abstract

Substituted phenols, anilines, pyridines and mononitrobenzenes can be classified as polar narcotics. These chemicals differ from non-polar narcotic compounds not only in their toxic potency (normalized by log Kow), but also in their Fish Acute Toxicity Syndrome profiles, together suggesting a different mode of action.

For 97 polar narcotics, which are not ionized under physiological conditions, 11 physico-chemical and quantum-chemical descriptors were calculated. Using principal component analysis, 91 % of the total variance in this descriptor space could be explained by three principal components which were subsequently used as factors in a statistical design. Eleven compounds were selected based on a two-level full factorial design including three compounds near the center of the chemical domain (a 23+3 design).

QSARs were developed for both the design set and the whole set of 63 polar narcotics for which guppy and/or fathead minnow data were available in the literature. Both QSARs, based on partial least squares regression (3 latent variables), resulted in good models (R2=0.96 and Q2=0.82; R2=0.86 and Q2=0.83 respectively) and provided similar pseudo-regression coefficients. In addition, the model based on the design chemicals was able to predict the toxicity of the 63 compounds (R2 =0.85).

Models show that acute fish toxicity is determined by hydrophobicity, HOMO-LUMO energy gap and hydrogen-bond acceptor capacity.

Keywords

Fish acute LC50 PCA PLS polar narcosis QSAR statistical design 

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Copyright information

© Ecomed Publishers 1997

Authors and Affiliations

  • Eñaut Urrestarazu Ramos
    • 1
  • Wouter H. J. Vaes
    • 1
  • Henk J. M. Verhaar
    • 1
  • Joop L. M. Hermens
    • 1
  1. 1.Research Institute of Toxicology (RITOX)Utrecht UniversityTD UtrechtThe Netherlands

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