Omega-N: Interpretable Structural Node Descriptors and Their Applicability Domain

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.

Networks describe systems in biology and beyond, from protein interactions and social relationships to power grids and citation records. Reasoning about such systems requires understanding their structure: which elements are central, which connections bridge separate communities, and how it changes when elements are removed. Although large language models (LLMs) excel at natural language, they struggle with such questions when networks are given as edge lists, sentences or measurement tables, because their structural meaning must be inferred. Here we introduce BioGlyph, which compiles network topology into an interpretable and transferable language of structural roles. BioGlyph combines graph partitioning and structural measurements to identify roles such as hubs, community cores and cross-community connectors, and fixed rules to translate them into a universal vocabulary. The representation describes each element through its structural role, supporting evidence and semantic consequences, leaving both the network and the LLM unchanged. Across twenty networks spanning five domains, BioGlyph substantially improves open LLMs' ability to answer structural reasoning questions, outperforming edge-based, numerical and learned representations by up to 26 percentage points in system accuracy. Ablations show that the gain comes from explicitly encoding structural roles in semantically interpretable terms. The gain is more prominent in dense, community-structured networks and diminishes in sparse networks whose topology is more readily inferred from text. In a budding-yeast protein-interaction network, BioGlyph exposes biological organization: cross-community connectors are enriched for essential genes, whereas peripheral proteins are depleted. BioGlyph thus provides an interpretable representation for both language models and scientists to reason about network structure.

Graphs are a central representation in biomedical research, capturing molecular interaction networks, gene regulatory circuits, cell--cell communication maps, and knowledge graphs. Despite their importance, currently there is not a broadly reusable foundation model available for graph analysis comparable to those that have transformed language and vision. Existing graph neural networks are typically trained on a single dataset and learn representations specific only to that graph's node features, topology, and label space, limiting their ability to transfer across domains. This lack of generalization is particularly problematic in biology and medicine, where networks vary substantially across cohorts, assays, and institutions. Here we introduce a graph foundation model designed to learn transferable structural representations that are not specific to specific node identities or feature schemes. Our approach leverages feature-agnostic graph properties, including degree statistics, centrality measures, community structure indicators, and diffusion-based signatures, and encodes them as structural prompts. These prompts are integrated with a message-passing backbone to embed diverse graphs into a shared representation space. The model is pretrained once on heterogeneous graphs and subsequently reused on unseen datasets with minimal adaptation. Across multiple benchmarks, our pretrained model matches or exceeds strong supervised baselines while demonstrating superior zero-shot and few-shot generalization on held-out graphs. On the SagePPI benchmark, supervised fine-tuning of the pretrained backbone achieves a mean ROC-AUC of 95.5%, a gain of 21.8% over the best supervised message-passing baseline. The proposed technique thus provides a unique approach toward reusable, foundation-scale models for graph-structured data in biomedical and network science applications.