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Targeting comorbid diseases via network endopharmacology

Juaquim Aguirre-Plans, Janet Piñero, Jörg Menche, Ferran Sanz, Laura I Furlong, Harald H. H. W. Schmidt, Baldo Oliva, Emre Guney
doi: https://doi.org/10.1101/313809
Juaquim Aguirre-Plans
1Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, 08003, Spain
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Janet Piñero
1Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, 08003, Spain
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Jörg Menche
2CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, A-1090 Vienna, Austria
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Ferran Sanz
1Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, 08003, Spain
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Laura I Furlong
1Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, 08003, Spain
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Harald H. H. W. Schmidt
3Department of Pharmacology and Personalised Medicine, CARIM, FHML, Maastricht University, 6229 ER Maastricht, The Netherlands
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Baldo Oliva
1Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, 08003, Spain
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Emre Guney
1Research Programme on Biomedical Informatics, the Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, 08003, Spain
3Department of Pharmacology and Personalised Medicine, CARIM, FHML, Maastricht University, 6229 ER Maastricht, The Netherlands
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  • For correspondence: emre.guney@upf.edu
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Abstract

The traditional drug discovery paradigm has shaped around the idea of “one target, one disease”. Recently, it has become clear that not only it is hard to achieve single target specificity but also it is often more desirable to tinker the complex cellular network by targeting multiple proteins, causing a paradigm shift towards 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 targeting common biological pathways involved in diseases, giving rise to “endopharmacology” (multiple targets, multiple diseases). In this study, leveraging powerful network medicine tools, we describe a recipe for first, identifying common pathways pertaining to diseases and then, prioritizing drugs that target these pathways towards endopharmacology. We present proximal pathway enrichment analysis (PxEA) that uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs for their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. As a proof of principle, we focus on nine autoimmune disorders and using PxEA, we show that many drugs indicated for these conditions are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide the high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two phenotypes that have recently gained attention due to the increased comorbidity among patients.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 04, 2018.
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Targeting comorbid diseases via network endopharmacology
Juaquim Aguirre-Plans, Janet Piñero, Jörg Menche, Ferran Sanz, Laura I Furlong, Harald H. H. W. Schmidt, Baldo Oliva, Emre Guney
bioRxiv 313809; doi: https://doi.org/10.1101/313809
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Targeting comorbid diseases via network endopharmacology
Juaquim Aguirre-Plans, Janet Piñero, Jörg Menche, Ferran Sanz, Laura I Furlong, Harald H. H. W. Schmidt, Baldo Oliva, Emre Guney
bioRxiv 313809; doi: https://doi.org/10.1101/313809

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