Computational drug target prioritization in trypanosomatids.

COSENTINO RO; MAGARIÑOS MP; AGÜERO F

Mar del Plata

Congreso; Congreso Argentino de Protozoologia y Enfermedades Parasitarias; 2011

Sociedad Argentina de Protozoologia

Computational drug target prioritization in trypanosomatids COSENTINO R, MAGARIÑOS MP, AGÜERO FG. Instituto de Investigaciones Biotecnológicas, UNSAM. fernan@unsam.edu.ar In our lab we developed a computational tool, available online (the TDR Targets Database, http://tdrtargets.org) that facilitates the task of identification and prioritization of targets in complete genomes from pathogens causing neglected tropical diseases. This tool allows the filtering and ranking of genes through the assignment of scores to features (known or predicted) from each gene and fromtheir orthologs. Using this tool we made a prioritization of potential chemotherapeutic targets in T.brucei. In this prioritization we gave more relevance (higher score) to genes with only one copy (to facilitate downstream genetic experiments), with orthologs in yeast and/or E. coli that produce essentiality phenotypes when they are eliminated, among other features. From the resulting list, we selected the top 200 genes, which were analyzed individualy to search for additional biochemical and/or genetic information in the literature. Those genes which were already experimentally validated as drug targets in trypanosomatids or that are currently being studied by other labs were manually filtered to avoid overlaps. After this stage we selected five genes (a NAD synthase, a vitamin K epoxide reductase, a carbonic anhydrase, a putative transcription factor, and a gene of unknown function) for which we started our experimental validation process through iRNA knock-down in T.brucei. Additionally, for these genes we performed a computational search of potential inhibitory compounds. This was done by searching in TDRtargets for chemically modulated genes (those genes associated with compounds with significant activity (IC50, EC50 o KI < 2 uM)) that were homologs of our selected genes. In this work, we will discuss the results of the drug target prioritization strategy; the progress made in the experimental validation; and the selected chemical leads identified. Funded by Agencia Nacional de Promoción Científica y Tecnológica (PICT-2010-1479), Special Programme for Research and Training in Tropical Diseases (TDR, OMS A50830), and the Fogarty International Center ( Grant Number D43TW007888).