Toward a unifying strategy for the structure-based prediction of toxicological endpoints

Most computational methods used for the prediction of toxicity endpoints are based on the assumption that similar compounds have similar biological properties. This principle can be exploited using computational methods like read across or quantitative structure-activity relationships. However, there is no general agreement about which method is the most appropriate for quantifying compound similarity neither for exploiting the similarity principle in order to obtain reliable estimations of the compound properties. Moreover, optimal similarity metrics and modeling methods might depend on the characteristics of the endpoints and training series used in each case. This study describes a comparative analysis of the predictive performance of diverse similarity metrics and modeling methods in toxicological applications. A collection of two quantitative (n = 660, n = 1114) and three qualitative (n = 447, n = 905, n = 1220) datasets representing very different endpoints of interest in drug safety evaluation and rigorous methods were used to estimate the external predictive ability in each case. The results confirm that no single approach produces the best results in all instances, and the best predictions were obtained using different tools in different situations. The trends observed in this study were exploited to propose a unifying strategy allowing the use of the most suitable method for every compound. A comparison of the quality of the predictions obtained by the unifying strategy with those obtained by standard prediction methods confirmed the usefulness of the proposed approach.