Interactive online application for the prediction, ranking and prioritisation of drug targets in Schistosoma haematobium

Andreas J Stroehlein,Robin B Gasser,Ross S Hall,Neil D Young

doi:10.1186/s13071-018-3197-6

Abstract

BackgroundHuman schistosomiasis is a neglected tropical disease caused by parasitic worms of the genus Schistosoma that still affects some 200 million people. The mainstay of schistosomiasis control is a single drug, praziquantel. The reliance on this drug carries a risk of resistance emerging to this anthelmintic, such that research towards alternative anti-schistosomal drugs is warranted. In this context, a number of studies have employed computational approaches to prioritise proteins for investigation as drug targets, based on extensive genomic, transcriptomic and small-molecule data now available.MethodsHere, we established a customisable, online application for the prioritisation of drug targets and applied it, for the first time, to the entire inferred proteome of S. haematobium. This application enables selection of weighted and ranked proteins representing potential drug targets, and integrates transcriptional data, orthology and gene essentiality information as well as drug-drug target associations and chemical properties of predicted ligands.ResultsUsing this application, we defined 25 potential drug targets in S. haematobium that associated with approved drugs, and 3402 targets that (although they could not be linked to any compounds) are conserved among a range of socioeconomically important flatworm species and might represent targets for new trematocides.ConclusionsThe online application developed here represents an interactive, customisable, expandable and reproducible drug target ranking and prioritisation approach that should be useful for the prediction of drug targets in schistosomes and other species of parasitic worms in the future. We have demonstrated the utility of this online application by predicting potential drug targets in S. haematobium that can now be evaluated using functional genomics tools and/or small molecules, to establish whether they are indeed essential for parasite survival, and to assist in the discovery of novel anti-schistosomal compounds.

Highlights

Human schistosomiasis is a neglected tropical disease caused by parasitic worms of the genus Schistosoma that still affects some 200 million people
We identified potential drug targets in S. haematobium that could be linked to approved drugs and inferred novel targets that are conserved among socioeconomically important parasitic flatworms, for which no known ligands exist
Online application to predict and prioritise drug targets in S. haematobium and to infer associated drugs To enable the customisable prioritisation of drug targets based on all inferred target/compound properties, we developed an online application using the shiny package [43] of the R programming language v.3.5.0, which allows for the inclusion of 29 gene/protein features (Table 1 and Fig. 1) in five different ways (Fig. 2)

Summary

Introduction

Human schistosomiasis is a neglected tropical disease caused by parasitic worms of the genus Schistosoma that still affects some 200 million people. The online resource TDRtargets [18], mainly established for unicellular pathogens, allows for the prediction of drug targets for a number of parasitic helminths that cause neglected tropical diseases [19, 20]. Another target prioritisation approach, which relies on both filtering and ranking of weighted gene/protein features, has been applied to predict kinases as drug targets in Haemonchus contortus, an economically important parasitic roundworm (nematode) [21]. We identified potential drug targets in S. haematobium that could be linked to approved drugs and inferred novel targets that are conserved among socioeconomically important parasitic flatworms, for which no known ligands exist

Results

Discussion

Conclusion