Prioritization of Potential Drugs Through Pathway-Based Drug Repurposing and Network Proximity Analysis

Belén Otero-Carrasco, Lucía Prieto Santamaría, Alejandro Rodríguez González

Abstract: Drug repurposing is an effective strategy to identify novel therapeutic options by leveraging existing drugs with known mechanisms of action and safety profiles. This work introduces a pathway-based drug repurposing approach that combines protein-protein interaction (PPI) networks and transcriptomic data to prioritize candidate drugs. The underlying assumption is that if disease 1 and disease 2 are both associated with the same biological pathway, then drugs known to be effective for disease 2 may be potential treatments for disease 1. To explore these relationships, disease–pathway–drug triplets are constructed. Genes shared between disease 1 and the associated pathway are identified, and their proximity is calculated within the PPI network using a Z-score based on random permutations. Candidate drugs for disease 2 are then analyzed using the Connectivity Map data, assessing whether their up- or down-regulated gene signatures are enriched for the genes contributing to the proximity between disease 1 and the pathway. This integration enables the ranking of candidate drugs based on their potential biological impact on disease 1. Finally, top-ranked drug–disease associations are evaluated through manual curation of the scientific literature to assess existing evidence supporting the proposed repurposing hypothesis.