Drug repurposing in idiopathic pulmonary fibrosis filtered by a bioinformatics-derived composite score

E Karatzas,G Kolios,G M Spyrou,M M Bourdakou

doi:10.1038/s41598-017-12849-8

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a rare disease of the respiratory system in which the lungs stiffen and get scarred, resulting in breathing weakness and eventually leading to death. Drug repurposing is a process that provides evidence for existing drugs that may also be effective in different diseases. In this study, we present a computational pipeline having as input a number of gene expression datasets from early and advanced stages of IPF and as output lists of repurposed drugs ranked with a novel composite score. We have devised and used a scoring formula in order to rank the repurposed drugs, consolidating the standard repurposing score with structural, functional and side effects’ scores for each drug per stage of IPF. The whole pipeline involves the selection of proper gene expression datasets, data preprocessing and statistical analysis, selection of the most important genes related to the disease, analysis of biological pathways, investigation of related molecular mechanisms, identification of fibrosis-related microRNAs, drug repurposing, structural and literature-based analysis of the repurposed drugs.

Highlights

Idiopathic Pulmonary Fibrosis (IPF) is a rare, incurable disease of the respiratory system during which fibrotic tissue and scars appear in the lungs
For the last part of our study, we searched for microRNAs that are related to fibrotic diseases in HMDD v2.0 (Human microRNA Disease Database version 2.0)[77,78] (Table 12)
We present a bioinformatics pipeline that analyses IPF gene expression data on early and advanced stages of the disease deriving candidate repurposed drugs for IPF and for each stage respectively

Summary

Introduction

IPF is a rare, incurable disease of the respiratory system during which fibrotic tissue and scars appear in the lungs. Recent biological pathway-related drug repurposing studies for IPF suggest promising results. This study’s main contribution is the presentation of a bioinformatics pipeline for computational drug repurposing that ends with re-ranking of the repurposed drugs according to a composite drug repurposing score (CoDReS) This score aims to combine the classical drug repurposing inhibition score with other major components related to the suitability of a drug/chemical compound to be successfully applied to the disease under study. The present study is targeting IPF through the aforementioned computational drug repurposing pipeline and concludes to candidate drugs (some of which are natural products), significant genes, microRNAs and pathways functionally related to IPF. We use the top differentially expressed genes, the resulted repurposed drugs along with their targets and fibrosis-related microRNAs to better understand the mechanisms and the biological pathways perturbed by IPF

Methods

Results

Conclusion