Biomedical Chemistry: Research and Methods, 2018, 1(3), e00019
The 40th Anniversary of the Institute of Physiologically Active Compounds of the Russian Academy of Sciences

QSAR Modeling of Acute Neurotoxicity of Some Organic Solvents with Respect to Rodents

V.Yu. Grigorev*, O.E. Raevskaya, A.V. Yarkov, O.A. Raevsky

Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia;*e-mail: beng@ipac.ac.ru

Key words: acute neurotoxicity; QSAR; HYBOT

DOI: 10.18097/BMCRM00019

The whole version of this paper is available in Russian.

Using literature data analysis, the regression models of acute sublethal neurotoxicity of 47 organic solvents with respect to rats and mice have been developed. To construct the models, we used linear regression, random forest and support vector machines approaches. The linear regression equations were selected as the best models. They are designed on the basis of four molecular descriptors: polarizability, sum of positive atom charges, sum of proton acceptor descriptors and dipole moment. The developed models have good descriptive and predictive ability and clear physicochemical interpretation.

Nhe structure of the compounds was described using fifteen physico-chemical descriptors to describe including polarizability, partial atomic charges, hydrogen bond descriptors calculated on the basis of the HYBOT program [10], lipophilicity [11] and dipole moment [12]. The following statistical methods were used to create the regression models: linear regression (LR), random forest (RF), support vector machine (SVM) realized in the corresponding computer programs: SVD [13], rrforest [14] and flssvm [15]. As the statistical characteristics of the models the next parameters were taken: n - number of molecules, m – number of descriptors, r2 – square of the linear correlation coefficient, s – standard deviation, q2 and scv – square of the linear correlation coefficient and standard deviation in condition of cross-validation for k-blocks (k=10, 100 iterations). Standard errors were used to estimate the error of the LR model coefficients. Regression models were calculated by examinations of all possible combinations of 1-5 descriptors. The best models were determined by the minimum value of s. In the case of close values of s, models with smaller values of m were preferred. A simple approach was used to determine the applicability domain (AD) of models, which consisted in calculation of the intervals of changing of dependent and independent variables.

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Table 1. Statistical properties of neurotoxicity models against rats.

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Table 2. Statistical properties of neurotoxicity models against mice.

ACKNOWLEDGEMENTS

The work was carried out within the framework of the state task for 2018 (topic number 0090-2017-0020).

SUPPLEMENTARY

Supplementary materials are available at http://dx.doi.org/10.18097/BMCRM00019

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