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Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology

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 patien...

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Autores principales: Aguirre-Plans, Joaquim, Piñero, Janet, Menche, Jörg, Sanz, Ferran, Furlong, Laura I., Schmidt, Harald H. H. W., Oliva, Baldo, Guney, Emre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160959/
https://www.ncbi.nlm.nih.gov/pubmed/29932108
http://dx.doi.org/10.3390/ph11030061
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author Aguirre-Plans, Joaquim
Piñero, Janet
Menche, Jörg
Sanz, Ferran
Furlong, Laura I.
Schmidt, Harald H. H. W.
Oliva, Baldo
Guney, Emre
author_facet Aguirre-Plans, Joaquim
Piñero, Janet
Menche, Jörg
Sanz, Ferran
Furlong, Laura I.
Schmidt, Harald H. H. W.
Oliva, Baldo
Guney, Emre
author_sort Aguirre-Plans, Joaquim
collection PubMed
description 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.
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spelling pubmed-61609592018-10-01 Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology Aguirre-Plans, Joaquim Piñero, Janet Menche, Jörg Sanz, Ferran Furlong, Laura I. Schmidt, Harald H. H. W. Oliva, Baldo Guney, Emre Pharmaceuticals (Basel) Article 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. MDPI 2018-06-22 /pmc/articles/PMC6160959/ /pubmed/29932108 http://dx.doi.org/10.3390/ph11030061 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Aguirre-Plans, Joaquim
Piñero, Janet
Menche, Jörg
Sanz, Ferran
Furlong, Laura I.
Schmidt, Harald H. H. W.
Oliva, Baldo
Guney, Emre
Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
title Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
title_full Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
title_fullStr Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
title_full_unstemmed Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
title_short Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
title_sort proximal pathway enrichment analysis for targeting comorbid diseases via network endopharmacology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160959/
https://www.ncbi.nlm.nih.gov/pubmed/29932108
http://dx.doi.org/10.3390/ph11030061
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