XML-CIMT: Explainable Machine Learning (XML) Model for Predicting Chemical-Induced Mitochondrial Toxicity.

Organ toxicity caused by chemicals is a serious problem in the creation and usage of chemicals such as medications, insecticides, chemical products, and cosmetics. In recent decades, the initiation and development of chemical-induced organ damage have been related to mitochondrial dysfunction, among several adverse effects. Recently, many drugs, for example, troglitazone, have been removed from the marketplace because of significant mitochondrial toxicity. As a result, it is an urgent requirement to develop in silico models that can reliably anticipate chemical-induced mitochondrial toxicity. In this paper, we have proposed an explainable machine-learning model to classify mitochondrially toxic and non-toxic compounds. After several experiments, the Mordred feature descriptor was shortlisted to be used after feature selection. The selected features used with the CatBoost learning algorithm achieved a prediction accuracy of 85% in 10-fold cross-validation and 87.1% in independent testing. The proposed model has illustrated improved prediction accuracy when compared with the existing state-of-the-art method available in the literature. The proposed tree-based ensemble model, along with the global model explanation, will aid pharmaceutical chemists in better understanding the prediction of mitochondrial toxicity.

An Explainable Supervised Machine Learning Model for Predicting Respiratory Toxicity of Chemicals Using Optimal Molecular Descriptors.

Respiratory toxicity is a serious public health concern caused by the adverse effects of drugs or chemicals, so the pharmaceutical and chemical industries demand reliable and precise computational tools to assess the respiratory toxicity of compounds. The purpose of this study is to develop quantitative structure-activity relationship models for a large dataset of chemical compounds associated with respiratory system toxicity. First, several feature selection techniques are explored to find the optimal subset of molecular descriptors for efficient modeling. Then, eight different machine learning algorithms are utilized to construct respiratory toxicity prediction models. The support vector machine classifier outperforms all other optimized models in 10-fold cross-validation. Additionally, it outperforms the prior study by 2% in prediction accuracy and 4% in MCC. The best SVM model achieves a prediction accuracy of 86.2% and a MCC of 0.722 on the test set. The proposed SVM model predictions are explained using the SHapley Additive exPlanations approach, which prioritizes the relevance of key modeling descriptors influencing the prediction of respiratory toxicity. Thus, our proposed model would be incredibly beneficial in the early stages of drug development for predicting and understanding potential respiratory toxic compounds.

Prediction of Drug-Induced Liver Toxicity Using SVM and Optimal Descriptor Sets.

Drug-induced liver toxicity is one of the significant safety challenges for the patient's health and the pharmaceutical industry. It causes termination of drug candidates in clinical trials and also the retractions of approved drugs from the market. Thus, it is essential to identify hepatotoxic compounds in the initial stages of drug development process. The purpose of this study is to construct quantitative structure activity relationship models using machine learning algorithms and systematical feature selection methods for molecular descriptor sets. The models were built from a large and diverse set of 1253 drug compounds and were validated internally with 10-fold cross-validation. In this study, we applied a variety of feature selection techniques to extract the optimal subset of descriptors as modeling features to improve the prediction performance. Experimental results suggested that the support vector machine-based classifier had achieved a better classification accuracy with reduced molecular descriptors. The final optimal model provides an accuracy of 0.811, a sensitivity of 0.840, a specificity of 0.783 and Mathew's correlation coefficient of 0.623 with an internal validation set. Furthermore, this model outperformed the prior studies while evaluated in both the internal and external test sets. The utilization of distinct optimal molecular descriptors as modeling features produce an in silico model with a superior performance.