ProbeMatchDTI: Probe-Driven Multi-Scale Biochemical Pattern Matching for Drug-Target Interaction Prediction

Abstract

Drug-target interaction (DTI) prediction is an important task in AI-driven drug discovery. Although recent biochemical representation learning methods have improved DTI prediction, their passive feature aggregation tends to favor dominant molecular patterns while suppressing weak yet binding-relevant signals, such as functional groups and residue-context patterns, limiting the modeling of multi-scale biochemical correspondences. To address this issue, we propose ProbeMatchDTI, a pattern-probe-driven framework comprising IterProbe and BindingProbe. IterProbe explicitly retains contextual states across refinement depths and uses learnable probes to select them at each position before cross-entity matching, thereby preserving weak biochemical patterns and strengthening associations among functional groups, local motifs, and molecular scaffolds. BindingProbe then characterizes cross-entity drug-protein complementarity at local biochemical-unit and whole-pair levels, jointly modeling fine-grained interactions and multi-scale correspondences while preserving weaker binding-relevant associations. Extensive experiments demonstrate the superiority of ProbeMatchDTI, achieving 2.0% and 0.5% higher AUC-ROC on BindingDB and DrugBank, respectively. Feature-level pattern analyses further characterize its probe-driven behavior in cross-scale biochemical pattern matching. We further connect ProbeMatchDTI predictions with an evidence-guided downstream drug-discovery workflow, demonstrating their utility for candidate refinement and validation planning. Our code is available at https://github.com/developer-hq/ProbeMatchDTI