A Knowledge‐Guided Graph Learning Approach Bridging Phenotype‐ and Target‐Based Drug Discovery

Discovering therapeutic molecules requires the integration of both phenotype-based drug discovery (PDD) and target-based drug discovery (TDD). However, this integration remains challenging due to the inherent heterogeneity, noise, and bias present in biomedical data. In this study, Knowledge-Guided Drug Relational Predictor (KGDRP), a graph representation learning approach is developed that effectively integrates multimodal biomedical data, including network data containing biological system information, gene expression data, and sequence data that incorporates chemical molecular structures, all within a heterogeneous graph (HG) structure. By incorporating biomedical HG (BioHG) into a heterogeneous graph neural network (HGNN)-based architecture, KGDRP exhibits a remarkable 12% improvement compared to previous methods in real-world screening scenarios. Notably, the biology-informed representation, derived from KGDRP, significantly enhance target prioritization by 26% in drug target discovery. Furthermore, zero-shot evaluation on COVID-19 exhibited a notably higher success rate in identifying diverse potential drugs. The utilization of BioHG facilitates a unique KGDRP-based analysis of cell-target-drug interactions, thereby enabling the elucidation of drug mechanisms. Overall, KGDRP provides a robust infrastructure for the seamlessly integration of multimodal data and biomedical networks, effectively accelerating PDD, guiding therapeutic target discovery, and ultimately expediting therapeutic molecule discovery.