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Polar narcosis: Designing a suitable training set for QSAR studies

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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.

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Correspondence to Eñaut Urrestarazu Ramos.

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Ramos, E.U., Vaes, W.H.J., Verhaar, H.J.M. et al. Polar narcosis: Designing a suitable training set for QSAR studies. Environ. Sci. & Pollut. Res. 4, 83–90 (1997). https://doi.org/10.1007/BF02986285

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Keywords

  • Fish acute LC50
  • PCA
  • PLS
  • polar narcosis
  • QSAR
  • statistical design