A MULTILAYER NETWORK APPROACH FOR GUIDING DRUG REPURPOSING IN NEGLECTED DISEASES

MAGARIÑOS MP; BERENSTEIN AJ; CHERNOMORETZ A; AGÜERO F

Mar del Plata

Congreso; X Congreso de Protozoología y Enfermedades Parasitarias; 2014

Sociedad Argentina de Protozoología y Enfermedades Parasitaria

Historically, lack of interest from the pharmaceutical industry, resulted in the lack of drugs for the majority of the pathogens that cause neglected diseases. With the advent of open chemical resources and the release of data from high throughput screenings the availability of chemical information has increased greatly. However most of the information on targets and the activity of drugs is for humans or model organisms. This creates a huge opportunity for computational exercises that use comparative genomics and chemogenomic approaches. In this work we use a multilayer network strategy to model a map of bioactive drugs, their targets, and other infromative relationships. Using chemical datasets containing bioactivity data for pathogen and non-pathogen targets we built a three-layer network containing three disjoint sets of vertexes with 1) 1.5 million drugs; 2) 167,000 proteins across 221 species; and 3) three affiliation-type protein features (orthology, Pfam domains, participation in metabolic pathways). Only statistically significant features (in the context of drug-target predictions) were taken into account. A bipartite projection of the protein layer was obtained capturing the protein affiliations to different annotation classes. Using this network model, we tackled the problems of i) prioritizing targets for drug discovery for pathogens; and ii) suggesting candidate targets for orphan compounds (those that are active in whole-cell screenings but whose target is currently unknown). We used a tenfold cross validation procedure to assess the performance of the network to prioritize relevant targets and show that he method overcomes traditional similarity-based searches against druggable targets. In the presentation we will discuss some of the top ranked proteins. We also used obtained candidate target proteins for orphan molecules that were active in whole-cell assays against P. falciparum and will discuss the proposed targets that mediate the antiplasmodial activity for some of these orphan compounds.