<html> <head> </head> <body> QSAR for algae toxicity of benzene derivatives </body> </html> <html> <head> </head> <body> </body> </html> <html> <head> </head> <body> 07.12.2009 </body> </html> <html> <head> </head> <body> </body> </html> <html> <head> </head> <body> </body> </html> <html> <head> </head> <body> 09.01.2010 </body> </html> <html> <head> </head> <body> Model is proprietary, but the training and test sets are available. </body> </html> <html> <head> </head> <body> None to date. </body> </html> <html> <head> </head> <body> Chlorella vulgaris </body> </html> <html> <head> </head> <body> EU testing method C.3. The EC50 is the concentration (mM) that induces toxicity response halfway between the baseline and maximum after 15 min. </body> </html> <html> <head> </head> <body> mM </body> </html> <html> <head> </head> <body> log(1/EC50) </body> </html> <html> <head> </head> <body> Toxicity data [log(1/EC50)] were determined in a biochemical assay utilizing the unicellular alga C. vulgaris. Algae in the logarithmic phase of their growth cycle were used. All toxicological analyses were performed in a buffer solution with a pH of 6.9 and a temperature between 25 and 30 °C. Assays were conducted following the protocol described by Worgan et al. (2003) with a 15 min static design. The disappearance of FDA was accounted for by spectrofluorimetric measurement of fluorescein (the product of hydrolysis) (Leszczynska & Oleszkiewic 1996) at an excitation wavelength of 465 nm and an emission wavelength of 515 nm. Range-finding experiments were performed in order to determine the highest and lowest concentrations required to produce a dose-response relationship ranging from 100% inhibition of enzyme activity to no observed toxicological effect. Blank buffer solution was utilized as a control, and the relative responses to it were used to generate the dose-response curve. The 50% effective concentration was estimated by Probit analysis using the SPSS ver. 10.0 (SPSS Inc., Chicago, IL) software. The average EC50 was taken from a minimum of three analyses. </body> </html> <html> <head> </head> <body> The toxicity data are taken from one publication (Cronin et al, 2004) to ensure consistency. The data were generated in on one lab and in one experimental series. Statistics: max value: 3.1 min value: -4.06 standard deviation: 1.465 skewness: -0.422 </body> </html> <html> <head> </head> <body> QSAR </body> </html> <html> <head> </head> <body> log(1/EC50) = -3.532 +0.371*Kier&Hall index (order 0) +1.233*Number of benzene rings -23.698*Difference (Pos - Neg) in Charged Part of Partial Charged Surface Area (Zefirov) -22.954*HA dependent HDCA-2/SQRT(TMSA) (Zefirov) (all) </body> </html> <html> <head> </head> <body> Initial pool of ~1000 descriptors. Stepwise descriptor selection based on a set of statistical selection rules: one-parameter equations: Fisher criterion and R2 over threshold, variance and t-test value over threshold, intercorrelation with another descriptor not over threshold; two-parameter equations: intercorrelation coefficient below threshold, significant correlation with endpoint, in terms of correlation coefficient and t-test. Stepwise trial of additional descriptors not significantly correlated to any already in the model. </body> </html> <html> <head> </head> <body> 1D, 2D, and 3D theoretical calculations. Quantum chemical descriptors derived from AM1 calculation. Model developed by using multilinear regression. </body> </html> <html> <head> </head> <body> 18.25 (73 chemicals /4 descriptors) </body> </html> <html> <head> </head> <body> Applicability domain based on training set: a) by chemical identity: benzene derivatives with one aromatic core b) by descriptor value range: The model is suitable for compounds that have the descriptors in the following minimal-maximal ranges: Kier&Hall index (order 0): 1.45 - 13.9 Number of benzene rings: 0 - 2 Difference (Pos - Neg) in Charged Part of Partial Charged Surface Area (Zefirov): -0.0593 - 0.00616 HA dependent HDCA-2/SQRT(TMSA) (Zefirov) (all): 0 - 0.0655 </body> </html> <html> <head> </head> <body> Range of descriptor values in training set with ±30% confidence. Descriptor values must fall between maximal and minimal descriptor values of training set ±30%. </body> </html> <html> <head> </head> <body> See 5.1 </body> </html> <html> <head> </head> <body> 73 data points: 34 negative values; 39 positive values </body> </html> <html> <head> </head> <body> </body> </html> <html> <head> </head> <body> R2 = 0.921 (Correlation coefficient) s2 = 0.427 (Standard error of the estimate) F = 197.8 (Fisher function) </body> </html> <html> <head> </head> <body> R2CV = 0.904 </body> </html> <html> <head> </head> <body> R2CVMO = 0.903 </body> </html> <html> <head> </head> <body> </body> </html> <html> <head> </head> <body> </body> </html> <html> <head> </head> <body> ABC analysis (2:1 training : prediction) on sorted (in increased order of endpoint value) data divided into 3 subsets (A;B;C). Training set formed with 2/3 of the compounds (set A+B, A+C, B+C) and validation set consisted of 1/3 of the compounds (C, B, A). average R2 (fitting) = 0.923 average R2 (prediction) = 0.900 </body> </html> <html> <head> </head> <body> 18 data points: 9 negative values; 9 positive values </body> </html> <html> <head> </head> <body> From sorted data each 5th was subjected to the test set starting from 3rd in order to assure the equality in distribution tails. </body> </html> <html> <head> </head> <body> R2 = 0.887 (Coefficient of determination) </body> </html> <html> <head> </head> <body> Descriptor value range (all in range of applicability domain): Kier&Hall index (order 0): 3.57 - 12.9 Number of benzene rings: 0 - 2 Difference (Pos - Neg) in Charged Part of Partial Charged Surface Area (Zefirov): -0.0236 - 0.00995 HA dependent HDCA-2/SQRT(TMSA) (Zefirov) (all): 0.00548 - 0.0543 </body> </html> <html> <head> </head> <body> The validation coefficient of determination (R2) is close to the coefficients of internal validation (R2CV and R2CVMO). </body> </html> <html> <head> </head> <body> Descriptors "Kier&Hall index (order 0)" and "Number of benzene rings" define a non-polar narcosis. They cover the toxicity baseline that is usually modelled with logP. The descriptors "Difference (Pos - Neg) in Charged Part of Partial Charged Surface Area (Zefirov)" and "HA dependent HDCA-2/SQRT(TMSA) (Zefirov) (all)" are related to the reactivity of the compounds and they represent the polar narcosis part of the toxicity. </body> </html> <html> <head> </head> <body> A posteriori mechanistic interpretation, consistent with published scientific interpretations of experiments. </body> </html> <html> <head> </head> <body> Provided in Cronin et al (2004) </body> </html> <html> <head> </head> <body> Data taken from Cronin et al.(2004) </body> </html> Molcode, algae toxicity of benzene derivatives, Chlorella vulgaris