HierDTA: Hierarchical Structure-Aware Representation Learning for Drug–Target Affinity Prediction

Abstract

Drug–target affinity (DTA) prediction plays an important role in computer-aided drug discovery, where reliable computational models can help prioritize compound–protein pairs before experimental validation. A key challenge in DTA prediction is to effectively mine multilevel molecular information from drug structures while accurately modeling the binding-site environment of target proteins. To address these issues, we introduce HierDTA, a hierarchical structure-aware framework for DTA prediction. HierDTA represents each drug as an atom–motif heterogeneous graph and introduces an augmentation module that propagates functional-motif semantics to the corresponding atoms. For proteins, kinase domain structures are converted into residue interaction graphs. The resulting atom and residue representations are integrated using cross-attention to capture pair-specific relationships, while molecule fingerprints and pretrained ESM-2 embeddings provide complementary global information. Compared with state-of-the-art methods, HierDTA achieves superior performance on the Davis data set across all metrics and attains the highestrm2of 0.791 on KIBA. It also exhibits strong generalization under cold-start settings, particularly on KIBA, where MSE is reduced by 21.7% in the unseen-protein scenario. Ablation study and interpretability analysis supported the contributions of the hierarchical augmentation and interaction components. Case studies further showed that HierDTA provided early enrichment of candidate bioactive compounds. These results indicate that HierDTA is an effective framework for affinity prediction and target-specific virtual screening.