Polar narcosis: Designing a suitable training set for QSAR studies
- 130 Downloads
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.
KeywordsFish acute LC50 PCA PLS polar narcosis QSAR statistical design
Unable to display preview. Download preview PDF.
- J. L. M. Hermens in:Hutzinger, O. (Ed.): Handbook of Environmental Chemistry. Vol. 2E, Springer Verlag, Berlin 1989, pp. 111–162Google Scholar
- J. L. M. Hermens in:Karcher, W. andDevillers, J. (Eds.): Practical Applications of QSAR in Environmental Chemistry and Toxicology. Kluwer Academic Publishers, Dordrecht 1990, pp. 263–280Google Scholar
- M. Sjöström;L. Eriksson, in van de Waterbeemd, H. (Ed.): Methods and principles in medicinal chemistry. Vol. 2 (Chemometric Methods in Molecular Design), Verlag Chemie, Weinheim 1995, pp. 63–40Google Scholar
- G. D. Veith;S. J. Broderius in:Kaiser, K. L. E. (Ed.): QSAR in Environmental Toxicology- II, D. Reidel Publishing Company, Dordrecht 1986, pp. 385–391Google Scholar
- D. W. Roberts in:Kaiser, K.L.E. (Ed.): QSAR in Environmental Toxicology - II, D. Reidel Publishing Company, Dordrecht 1986, pp. 295–308Google Scholar
- V. K. Gombar in:Kaiser, K.L.E. (Ed.): QSAR in Environmental Toxicology - II, D. Reidel Publishing Company, Dordrecht 1986, pp. 125–133Google Scholar
- G. Bringmann;R. Z. Kühn: Wasser-Abwasser-Forsch. 10(5), 161–166(1977)Google Scholar
- W.Beirat der Bundesärztekammer: Deutsches Ärzteblatt 86(49), C2239–2241 (1989)Google Scholar
- R. Kühn et. al.: Forschungsbericht 10603052, Mrz (1988)Google Scholar
- J. Bol; H. J. M. Verhaar;. C. J. van Leeuwen; J. L. M. Hermens: Predictions of the Aquatic Toxicity of High-Production-Volume-Chemicals Part B: Predictions, Published by the Dutch Ministry of Housing, Spatial Planning and Environment (1993)Google Scholar
- D. Leo;D. Weininger: MedChem Software Manual v Software, Day-Light Chemical Information Systems, Inc., Irvine CA, USA, (1989)Google Scholar
- US-EPA ERL-Duluth, Assessment Tools for the Evaluation of Risk (ASTER) v 1994: Software. US-EPA Environmental Research Laboratory-Duluth Scientific Outreach Program, Duluth MN, USA (1994)Google Scholar
- W. J. Hehre;L.D. Burke;A. J. Shusterman: Spartan User’s Guide, Wavefunction, Inc., Irvine CA, USA, (1993)Google Scholar
- B. M. Wise: PLS-Toolbox Version 1.3, Barry M. Wise, 1415 Wright Avenue, Richland WA, USA; email@example.com; obtained by anonymous FTP from ra.nrl.navy.mil:MacSciTech/chem/ chemometrics, February 1993, (1993)Google Scholar
- C. Moler;J. Little;S. Kleinman;S. Bangert: Matlab, Version 3.5, the MathWorks, Inc., Natick, MA (1992)Google Scholar
- S. Wold, in: van de Waterbeemd, (Ed.): Methods and principles in medicinal chemistry. Vol. 2 (Chemometric Methods in Molecular Design), Verlag Chemie, Weinheim 1995, pp. 195–218Google Scholar
- D. L. Massart;B. G. M. Vandeginste;S. N. Deming;Y. Michotte;L. Kaufman: in (Ed.)Vandeginste, B.G.M. andKaufman, L. (Eds.): Data handling in science and technology. Vol. 2 (Chemometrics: a textbook), Elsevier, Amsterdam 1988, pp. 47–48Google Scholar