Mitochondria are important organelles in human cells, providing more than 95% of the energy. However, some drugs and environmental chemicals could induce mitochondrial dysfunction, which might cause complex diseases and even worsen the condition of patients with mitochondrial damage. Some drugs have been withdrawn from the market due to their severe mitochondrial toxicity, such as troglitazone. Therefore, there is an urgent need to develop models that could accurately predict the mitochondrial toxicity of chemicals. In this paper, suitable data were obtained from literature and databases first. Then nine types of fingerprints were used to characterize these compounds. Finally, different algorithms were used to build models. Meanwhile, the applicability domain of the prediction models was defined. We have also explored the structural alerts of mitochondrial toxicity, which would be helpful for medicinal chemists to better predict mitochondrial toxicity and further optimize lead compounds.

Abstract Neurotoxicity is one of the main causes of drug withdrawal, and the biological experimental methods of detecting neurotoxic toxicity are time-consuming and laborious. In addition, the existing computational prediction models of neurotoxicity still have some shortcomings. In response to these shortcomings, we collected a large number of data set of neurotoxicity and used PyBioMed molecular descriptors and eight machine learning algorithms to construct regression prediction models of chemical neurotoxicity. Through the cross-validation and test set validation of the models, it was found that the extra-trees regressor model had the best predictive effect on neurotoxicity (${q}_{\mathrm{test}}^2$ = 0.784). In addition, we get the applicability domain of the models by calculating the standard deviation distance and the lever distance of the training set. We also found that some molecular descriptors are closely related to neurotoxicity by calculating the contribution of the molecular descriptors to the models. Considering the accuracy of the regression models, we recommend using the extra-trees regressor model to predict the chemical autonomic neurotoxicity.

Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of CYP2C8, which causes potential adverse drug events, cannot be neglected. The in vitro drug interaction studies guidelines for industry issued by the FDA also point out that it needs to be determined whether investigated drugs are CYP2C8 inhibitors before clinical trials. However, current studies mainly focus on predicting the inhibitors of other major P450 enzymes, and the importance of CYP2C8 inhibition has been overlooked. Therefore, there is a need to develop models for identifying potential CYP2C8 inhibition. In this study, in silico classification models for predicting CYP2C8 inhibition were built by five machine-learning methods combined with nine molecular fingerprints. The performance of the models built was evaluated by test and external validation sets. The best model had AUC values of 0.85 and 0.90 for the test and external validation sets, respectively. The applicability domain was analyzed based on the molecular similarity and exhibited an impact on the improvement of prediction accuracy. Furthermore, several representative privileged substructures such as 1H-benzo­[d]­imidazole, 1-phenyl-1H-pyrazole, and quinoline were identified by information gain and substructure frequency analysis. Overall, our results would be helpful for the prediction of CYP2C8 inhibition.

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