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

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

Published 2025 in bioRxiv

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.

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