Targeting comorbid diseases via network endopharmacology

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 Alzheimers disease, two phenotypes that have recently gained attention due to the increased comorbidity among patients.