Application of cross-validation strategies to avoid overestimation of performance of 2D-QSAR models for the prediction of aquatic toxicity of chemical mixtures

Abstract

ABSTRACT The quantitative structure–activity relationship (QSAR) modelling of mixtures is not as simple as that for individual chemicals, and it needs additional care to avoid overestimation of the performance. In this research, we have developed a 2D-QSAR model using only 2D interpretable and reproducible descriptors to predict the aquatic toxicity of mixtures of polar and non-polar narcotic substances present in the environment. Partial least squares (PLS) regression has been used to model the response variable (log 1/EC50 against Photobacterium phosphoreum) and the structural features of 84 binary mixtures of polar and nonpolar narcotic toxicants complying with the Organization of Economic Co-operation and Development (OECD) protocols. The model was cross-validated by mixtures-out and compounds-out cross-validation to nullify the developmental bias. The reliability of prediction of the model has been judged by the Prediction Reliability Indicator (PRI) tool using a newly designed set. The new model is robust, reproducible, extremely predictive, easily interpretable, and can be used for reliable prediction of aquatic toxicity of any untested chemical mixtures within the applicability domain. We have additionally used a machine learning-based chemical read-across algorithm in this study to improve the quality of predictions for the toxicity of the mixtures with the modelled descriptors.