Predictive Model for Drug-Induced Liver Injury Using Deep Neural Networks Based on Substructure Space

Drug-induced liver injury (DILI) is a major concern for drug developers, regulators, and clinicians. However, there is no adequate model system to assess drug-associated DILI risk in humans. In the big data era, computational models are expected to play a revolutionary role in this field. This study aimed to develop a deep neural network (DNN)-based model using extended connectivity fingerprints of diameter 4 (ECFP4) to predict DILI risk. Each data set for the predictive model was retrieved and curated from DILIrank, LiverTox, and other literature. The best model was constructed through ten iterations of stratified 10-fold cross-validation, and the applicability domain was defined based on integer ECFP4 bits of the training set which represented substructures. For the robustness test, we employed the concept of the endurance level. The best model showed an accuracy of 0.731, a sensitivity of 0.714, and a specificity of 0.750 on the validation data set in the complete applicability domain. The model was further evaluated with four external data sets and attained an accuracy of 0.867 on 15 drugs with DILI cases reported since 2019. Overall, the results suggested that the ECFP4-based DNN model represents a new tool to identify DILI risk for the evaluation of drug safety.