Closer to Biological Mechanism: Drug-Drug Interaction Prediction from the Perspective of Pharmacophore

Abstract Drug combinations are widely used in modern medicine but may cause severe adverse drug reactions. Therefore, making effective drug-drug interactions (DDI) prediction is crucial for pharmacovigilance. Existing DDI prediction models are typically built from a structural perspective, assuming that drugs with similar molecular structures may exhibit similar interactions. However, such approaches overlook the biological mechanisms underlying DDI in the human body. This not only weakens the generalization ability of the model, but also makes its interpretability less convincing. Inspired by this, we propose a new method called PC-DDI. Unlike structure-based models, PC-DDI utilizes pharmacophores as basic unit, and designs a complete pharmacophore feature processing framework. It further constructs a pharmacophore-based bipartite graph to model interactions between pharmacophores. This approach allows us to explore the underlying mechanisms of DDI from a functional perspective. We also design a spatial attention weight graph convolution module to optimize the message passing process by integrating pharmacophore position features with node features. Furthermore, we apply causal inference to identify key pharmacophores in pharmacophore bipartite graph, enhancing the interpretability. Compared with the SOTA, PC-DDI achieves an accuracy improvement of 1.84% under the transductive setting and consistently outperforms others in all other experiments.