TopoFuseNet: Hierarchical Graph Representation Learning with Multi-Scale Topological Features for Accurate Drug Synergy Prediction

Accurate prediction of drug synergy is paramount for developing effective combination therapies and advancing personalized medicine. Although methods based on graph neural networks (GNNs) have become a prevalent approach, they often treat molecules as flat graphs of connected atoms, thus overlooking their inherent hierarchical structure (i.e., atoms forming functional groups) and the critical topological information that governs molecular interactions. To address this limitation, we introduce TopoFuseNet, a novel hierarchical graph representation learning framework that integrates multi-scale topological features. The core innovations of TopoFuseNet include: 1) The first-ever application of “Group Centrality” from network science to cheminformatics, enabling the identification and quantification of functional groups crucial to drug activity; 2) A systematic, multi- path strategy to seamlessly integrate node-level (atom) and group-level (functional group) topological features into a Graph Attention Network (GAT) via feature augmentation, attention biasing, and hierarchical pooling; 3) A Differential Transformer module to deeply fuse multi-modal features learned from sequences, fingerprints, and our proposed hierarchical graph representations.

Extensive experiments on two large-scale benchmark datasets, DrugComb and DrugCombDB, demonstrate that TopoFuseNet significantly outperforms state-of-the-art methods across multiple key metrics, including AUC, AUPRC, and F1-score, while exhibiting exceptional generalization robustness under various stringent cold-start scenarios. In-depth ablation studies further confirm the effectiveness and necessity of each proposed innovative module. Furthermore, multi-scale interpretability analysis and zero-shot cross-domain transfer experiments reveal that the model successfully captures molecular interaction rules with clear pharmacological significance, demonstrating immense practical potential for discovering novel combination therapies through large-scale virtual screening. Our work not only delivers a superior model for drug synergy prediction, but more importantly, it establishes a novel and scalable paradigm for effectively integrating hierarchical molecular structures and topological information into GNNs.