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Pharmaceuticals (Basel). 2018 Jun 22;11(3). pii: E61. doi: 10.3390/ph11030061.

Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology.

Author information

1
Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain. joaquim.aguirre@upf.edu.
2
Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain. janet.pinero@upf.edu.
3
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, A-1090 Vienna, Austria. JMenche@cemm.oeaw.ac.at.
4
Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain. ferran.sanz@upf.edu.
5
Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain. laura.furlong@upf.edu.
6
Department of Pharmacology and Personalised Medicine, CARIM, FHML, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. h.schmidt@maastrichtuniversity.nl.
7
Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain. baldo.oliva@upf.edu.
8
Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain. emre.guney@upf.edu.
9
Department of Pharmacology and Personalised Medicine, CARIM, FHML, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. emre.guney@upf.edu.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; autoimmune disorders; comorbidity; drug repurposing; network endopharmacology; proximal pathway enrichment analysis; systems medicine; type 2 diabetes

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