CMF-ELN: A Cross-Modal-Fused End-to-end Learning Network for Cold-Start Drug-Drug Interaction Prediction

Cold-start drug–drug interactions (DDIs) prediction of new drugs is critical for minimizing unexpected adverse drug reactions. The crux of cold-start DDI prediction is to capture the Similarity between new and known drugs. However, such similarity is closely associated with complex relationships and mechanisms among drugs, enzymes, transporters, molecular structures, etc. Existing methods have three limitations in capturing such similarity: (1) only partial relationships and mechanisms are considered, which overlooks cross-modal information and yields incomplete or biased similarity modeling; (2) similarity computation between new and known drugs is conducted separately across modalities and performed offline for cold-start DDI prediction, leading to an increasing misalignment between the similarity computation and the DDI prediction stages; (3) existing interpretability analyses are typically single-modality and focus primarily on the key determinants of the perpetrator drug, while the underlying causes of susceptibility for the victim drug are seldom investigated. To address these issues, this paper proposes a novel Cross-Modal-Fused End-to-end Learning Network (CMF-ELN) with three components. First, diverse Multi-modal information is leveraged to construct four types of drug-centered knowledge graphs, enabling comprehensive similarity modeling between new and known drugs under reconstruction based supervision. Second, a four-channel graph autoencoder is designed to fuse cross-modal similarity within an end-to-end learning framework. Finally, a two-stage interpretability scheme is devised to precisely localize the key factors for both the perpetrator and the victim drugs. Extensive experiments on two real datasets demonstrate that CMF-ELN achieves significantly higher prediction accuracy and more comprehensive interpretability of mechanisms than its peers. The source code and datasets are publicly available in our GitHub repository: https://github.com/lhx-cmd/CMF-ELN.