Abstract
BACKGROUND: Polypharmacy's ability to circumvent acquired resistance to single drug makes it a critical strategy for treating complex diseases. However, it inevitably carries risks of drug-drug interactions (DDIs) that may alter pharmacological activities and potentially lead to severe adverse events or mortality. Computational assessment of drug combination has emerged as an effective approach to support clinical decision-making. Current risk identification methods focus on mining historical interaction patterns to uncover underlying mechanisms, yet face challenges from data sparsity. While data augmentation strategy can mitigate such problem, conventional approaches often introduce noise that obscures core pharmacological mechanisms, undermining safety evaluation. RESULTS: This study proposes a Multi-Mechanism Disentangled Drug-drug Interaction assessment framework integrated contrastive learning, MMDDI, which includes two key components: (1) biologically-informed multi-view generation that creates high-quality augmented views, effectively addressing semantic distortion during data augmentation; (2) Mechanism-aware disentanglement that incorporates mutual information constraints to isolate interaction mechanisms from coupling of multi-modal and heterogeneous data, eliminating quantification bias. Contrastive learning integrates labeled and unlabeled data to enhance robustness against sparse observations. CONCLUSIONS: Comprehensive evaluations demonstrate that MMDDI with hit@4 of 0.86 outperforms the compared baselines, with ablation studies validating the critical contributions of multi-view contrastive and mechanism disentanglement. MMDDI continues to demonstrate excellent performance in cold-start scenarios, achieving accuracy of 0.94 and recall of 0.95. Clinically, MMDDI enables interpretable causal analysis of drug interaction pathways through its mechanism-aware representations, providing operability for optimizing therapeutic regimens.