aiqbench analysis
HierDTA advances drug discovery by integrating hierarchical molecular graphs with protein residue interactions to improve the accuracy of predicting drug-target affinity. The framework demonstrates superior performance on standard benchmarks like Davis and KIBA, offering a robust tool for prioritizing compounds before expensive experimental validation. This work represents a significant step forward in using deep learning to model complex biological structures for virtual screening.
HierDTA: Hierarchical Structure-Aware Representation Learning for Drug--Target Affinity Prediction
arXiv:2610.27001v1 Announce Type: new 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 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 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.
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 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 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.
Machine Learning (cs.LG); Artificial Intelligence (cs.AI)
arXiv:2610.27001 [cs.LG]
(or arXiv:2610.27001v1 [cs.LG] for this version)
https://doi.org/10.48550/arXiv.2610.27001 Focus to learn more arXiv-issued DOI via DataCite
https://doi.org/10.1021/acsomega.6c07956 Focus to learn more DOI(s) linking to related resources
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