Multi-view knowledge-guided flow subgraphs with substructure initialization for explainable DDI prediction.

Polypharmacy has become essential in managing complex and chronic conditions, yet it introduces significant clinical risks due to potential drug-drug interactions (DDIs). Existing computational models struggle to provide accurate and interpretable predictions, largely due to fragmented integration of molecular structures and biomedical knowledge. These limitations arise from static graph designs, inadequate substructure modeling, and insufficient incorporation of semantic context, highlighting the need for a unified, explainable solution. In this study, we propose MKGFlow-DDI, a multi-view knowledge-guided framework that jointly leverages drug-drug interaction networks and biomedical knowledge graphs to dynamically construct drug-flow subgraphs. The model incorporates a dual-channel encoder designed to capture atom-level information and substructure-level features, integrating them with the global semantic embeddings of the composite network to derive novel feature representations. These representations are fused to initialize node features within each subgraph, which are iteratively optimized through similarity-based edge refinement to reduce noise and enhance biological relevance. To further improve generalization and stability, a contrastive learning module is introduced to align representations of perturbed subgraphs by maximizing consistency across positive and negative sample pairs. Experimental results on DrugBank and TWOSIDES demonstrate that MKGFlow-DDI outperforms state-of-the-art baselines, especially in scenarios involving previously unseen drugs. Additionally, the model produces interpretable semantic pathways that align with known pharmacological mechanisms, enabling clinically meaningful insights. Overall, MKGFlow-DDI establishes a robust and biologically grounded approach to DDI prediction, offering a promising direction for computational pharmacovigilance and personalized therapy optimization.