Computational Prediction of the Severity of Adverse Drug Reactions Caused by Drug–Drug Interactions

Background/Objectives: Adverse drug reactions (ADRs) caused by drug–drug interactions (DDIs) represent an important problem in pharmacotherapy, especially in patients receiving multiple medications. Most computational approaches to DDI-associated ADR prediction formulate the task as a binary classification, but they do not explicitly consider the severity of adverse reactions. Our study aims to develop structure-based models that predict the severity of ADRs associated with specific drug pairs. Methods: Datasets were generated using DrugMAP as the source of drug pair–ADR associations with annotated severity categories, and TwoSides was used as an additional source to generate conditionally negative examples. The drug pairs were represented using PoSMNA descriptors, which encode pair-specific structural features derived from the molecular structures of both compounds. Predictive models were built using PASS DDI software. Model performance was evaluated using a modified cross-validation procedure that excluded compound-level overlap between the training and test sets, thereby reducing information leakage caused by the repeated occurrence of the same drugs in different pairs. Results: Models were developed for 14 clinically relevant ADR types, including cardiovascular, hepatotoxic, nephrotoxic, hemorrhagic, metabolic, and neurological effects. The unweighted class-level macro-average AUC values ranged from 0.830 for the Major category to 0.911 for the Minor category, while balanced accuracy ranged from 0.776 to 0.857. Predictive performance varied significantly between ADR types and severity categories. Higher accuracy was observed for some ADR types that were better captured by the structure-based descriptors used in this study, whereas complex multifactorial reactions, such as hepatotoxicity, were less accurately predicted. Case-based assessment using clinically documented drug combinations showed that the predicted severity profiles were generally consistent with the expected clinical risk patterns. Conclusions: The proposed approach demonstrates that the PoSMNA descriptors of drug pairs can be used for preliminary prediction of DDI-associated ADR severity. The developed models can help to filter out potentially dangerous drug combinations at an early stage and are implemented in the AdverDDIPred web-application.