A graph retrieval-augmented generation pipeline for systematic drug target discovery: validation and application to...

The exponential growth of biomedical literature creates a cognitive bottleneck in drug target discovery, particularly for identifying therapeutically relevant mechanisms beyond established pathways. In ocular neovascularization, anti-VEGF therapies are standard of care, yet non-response and resistance remain critical unmet needs. We present an integrated computational framework combining Graph Retrieval-Augmented Generation (GraphRAG)-based literature mining, pathway co-localization analysis, and deep learning-based druggability assessment for systematic target prioritization. Using 5562 angiogenesis-related PubMed abstracts, we constructed a vascular knowledge graph (17 842 nodes; 9555 edges) and applied pathway co-localization with vascular endothelial growth factor A (VEGF-A) as a biological filter. As a validation step, the workflow recovered four targets-fibroblast growth factor 2, transforming growth factor-beta 1, interleukin-1 beta, and matrix metalloproteinase-9-already supported by clinical or advanced preclinical development, demonstrating concordance with expert-driven selection. Iterative querying subsequently identified two additional mechanistically supported candidates, fibroblast growth factor 1 and hepatocyte growth factor, sharing receptor tyrosine kinase-centered pathways with VEGF-A but lacking clinical evaluation in ocular neovascularization. Deep learning-based structural analysis (DeepSite and PocketMiner) identified high-confidence ligandable pockets for all six candidates. This work demonstrates how GraphRAG can systematically mine existing literature to recover known targets and surface literature-supported candidates that may be underprioritized for translational development. Rather than claiming de novo discovery, we emphasize the framework's utility as a scalable, transparent, and reproducible methodology for overcoming citation bias and literature overload. The workflow is generalizable to other complex, literature-rich disease domains.