PyrMol: A Knowledge-Structured Pyramid Graph Framework forGeneralizable Molecular Property Prediction

Abstract

Expert pharmaceutical chemists interpret molecular structures through a sophisticated cognitive hierarchy, transitioning from local functional moieties to spatial pharmacophores and, ultimately, to macroscopic pharmacological and physicochemical profiles. However, conventional Graph Neural Networks frequently overlook this high-level chemical intuition by treating molecules as single-scale atomic topology. To bridge this gap between human expertise and computational inference, we propose PyrMol, a knowledge-structured pyramid representation learning framework. By constructing heterogeneous hierarchical graphs, PyrMol orchestrates information flow across atomic, subgraph, and molecular levels. Crucially, the subgraph level systematically integrates three complementary expert views comprising functional groups, pharmacophores, and retrosynthetic fragments. To harmonize these explicit domain priors with implicit computational semantics, we introduce an adaptive Multi-source Knowledge Enhancement and Fusion module that dynamically balances their complementarity and redundancy. A Hierarchical Contrastive Learning strategy further ensures cross-scale semantic consistency. Empirical evaluations across ten benchmark datasets demonstrate that PyrMol outperforms 11 state-of-the-art baselines. Furthermore, its "plug-and-play" versatility provides a framework-agnostic performance boost for existing GNN architectures. PyrMol thus establishes a principled data-knowledge dual-driven paradigm for AI-aided Drug Discovery, effectively leveraging domain knowledge to catalyze advances in molecular property prediction.