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

Huangchao Xu, Baohua Zhang, Qian Liu, Zhong Jin, Yi Du

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 multi-level 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. \textcolor{black}{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 dataset across all metrics and attains the highest \(r_m^2\) of 0.791 on KIBA. It also exhibits…