h-MINT: Modeling Pocket-Ligand Binding with Hierarchical Molecular Interaction Network

摘要

Accurate molecular representations are critical for drug discovery, and a central challenge lies in capturing the chemical environment of molecular fragments, as key interactions, such as H-bond and π stacking, which occur only under specific local conditions. Most existing approaches represent molecules as atom-level graphs; however, individual atoms cannot express stereochemistry, lone pairs, conjugation, and other complex features. Fragment-based methods (e.g., principal subgraph or functional group libraries) fail to preserve essential information such as chirality, aromatic bond integrity, and ionic states. This work addresses these limitations from two aspects. (i) OverlapBPE tokenization. We propose a novel data-driven molecule tokenization method. Unlike existing approaches, our method allows overlapping fragments, reflecting the inherently fuzzy boundaries of small-molecule substructures and, together with enriched chemical information at the token level, thereby preserving a more complete chemical context. (ii) h- MINT model. We develop a hierarchical molecular interaction network capable of jointly modeling drug–target interactions at both atom and fragment levels. By supporting fragment overlaps, the model naturally accommodates the many-to- many atom–fragment mappings introduced by the OverlapBPE scheme. Extensive evaluation against state-of-the-art methods shows our method improves binding affinity prediction by 2-4% Pearson/Spearman correlation on PDBBind and LBA, enhances virtual screening by 1-3% in key metrics on DUD-E and LIT-PCBA, and achieves the best overall HTS performance on PubChem assays. Further analysis demonstrates that our method effectively captures interactive information while maintaining good generalization.