Complex Networks and the Drug Repositioning Problem

The contributions of model complexity, data volume, and feature modalities to knowledge graph-based drug repurposing remain poorly quantified under rigorous temporal validation. We constructed a pharmacology knowledge graph from ChEMBL 36 comprising 5,348 entities including 3,127 drugs, 1,156 proteins, and 1,065 indications. A strict temporal split was enforced with training data up to 2022 and testing data from 2023 to 2025, together with biologically verified hard negatives mined from failed assays and clinical trials. We benchmarked five knowledge graph embedding models and a standard graph neural network with 3.44 million parameters that incorporates drug chemical structure using a graph attention encoder and ESM-2 protein embeddings. Scaling experiments ranging from 0.78 to 9.75 million parameters and from 25 to 100 percent of the data, together with feature ablation studies, were used to isolate the contributions of model capacity, graph density, and node feature modalities. Removing the graph attention based drug structure encoder and retaining only topological embeddings combined with ESM-2 protein features improved drug protein PR-AUC from 0.5631 to 0.5785 while reducing VRAM usage from 5.30 GB to 353 MB. Replacing the drug encoder with Morgan fingerprints further degraded performance, indicating that explicit chemical structure representations can be detrimental for predicting pharmacological network interactions. Increasing model size beyond 2.44 million parameters yielded diminishing returns, whereas increasing training data consistently improved performance. External validation confirmed 6 of the top 14 novel predictions as established therapeutic indications. These results show that drug pharmacological behavior can be accurately predicted using target-centric information and drug network topology alone, without requiring explicit chemical structure representations.

Drug repurposing aims to identify new therapeutic uses for existing compounds and, compared with de novo drug discovery, offers a faster and more cost-effective path to clinical translation. However, the space of candidate drug-disease pairs is enormous and their underlying relationships often depend on complex multi-hop biological mechanisms, making it difficult to reliably predict which pairs represent true therapeutic relationships. Existing approaches tackle this from two directions: knowledge graph-based methods organize curated biomedical evidence into structured relational networks for grounded multi-hop reasoning, while LLM-based methods leverage pretrained knowledge to generate flexible mechanistic rationales. Yet neither is sufficient alone - KGs are confined to observed graph structure while LLMs lack factual grounding and risk hallucination. To address this gap, we propose DrugReason, a multi-view reasoning framework that integrates grounded KG reasoning with LLM-generated mechanistic inference for drug repurposing. DrugReason adaptively routes diverse reasoning paths to specialized experts conditioned on the query context, while a cross-expert distillation objective enables knowledge sharing without sacrificing expert specialization. Experiments on PharmaDB, DDInter, and DrugBank show that DrugReason improves average performance over strong single-view reasoning baselines and achieves competitive or superior results compared with graph-based alternatives, while providing interpretable routing-based predictions.

Drug repurposing is often framed as a candidate identification task, but existing approaches provide limited guidance for distinguishing biologically plausible candidates from historically well-connected ones. Here we introduce DrugKLM, a hybrid framework that integrates biomedical knowledge graph structure with large language model-based mechanistic reasoning to enable mechanistically grounded therapeutic prioritization. Across benchmark datasets, DrugKLM outperforms knowledge graph-only and language model-only baselines, including TxGNN. Beyond improved recall, DrugKLM confidence scores exhibit functional alignment with molecular phenotypes: higher scores are associated with transcriptional signatures linked to improved survival across 12 TCGA cancers. The scoring framework preferentially captures biologically perturbational signals rather than historical indication patterns. Expert curation across five cancers further reveals systematic differences in prioritization behavior, with DrugKLM elevating candidates supported by coherent mechanistic rationale and disease-specific clinical context. Together, these results establish DrugKLM as an evidence-integrative framework that translates heterogeneous biomedical data into mechanistically interpretable and clinically grounded therapeutic hypotheses.