The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of “one target, one disease” to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is to target common biological pathways involved in diseases via endopharmacology (multiple targets, multiple diseases). In this study, we present proximal pathway enrichment analysis (PxEA) for pinpointing drugs that target common disease pathways towards network endopharmacology. PxEA uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs by their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. Using PxEA, we show that many drugs indicated for autoimmune disorders are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two conditions that have recently gained attention due to the increased comorbidity among patients.

The authors received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 116030. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The authors also received support from EU H2020 Programme 2014–2020 under grant agreement No. 676559 (Elixir-Excelerate). E.G. was supported by EU-cofunded Beatriu de Pinós incoming fellowship from the Agency for Management of University and Research Grants (AGAUR) of Government of Catalunya and L.I.F. received support from ISCIII-FEDER (CPII16/00026). H.H.H.W.S. has received funding from from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 777111 (Repotrial). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001/0023, of the PE I+D+i 2013–2016, funded by ISCIII and FEDER. The DCEXS is a “Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370)