A chemogenomics strategy for discovery of chemical leads against parasites

MAGARIÑOS MP; CARMONA, SJ; AGÜERO F

Mar del Plata

Congreso; IX Congreso Argentino de Protozoologia y Enfermedades Parasitarias; 2011

Sociedad Argentina de Protozoologia

A chemogenomics strategy for discovery of chemical leads against parasites. María Paula Magariños, Santiago Carmona, and Fernán Agüero. Instituto de Investigaciones Biotecnológicas – Instituto Tecnológico de Chascomús, UNSAM - CONICET. The TDR Targets Database (http://tdrtargets.org) is a bioinformatics resource that facilitates the identification and prioritization of molecular targets for drug development, focusing on pathogens responsible for neglected human diseases. The database associates gene information from human pathogens with genomic and functional information from various sources. In order to expand the coverage of chemical information associated with targets from complete genomes, we integrated various chemical datasets into TDR Targets, associating them with protein targets based on a number of similarity-based rules. Compounds were obtained from three databases: DrugBank, PubChem and Starlite (ChEMBL). Using an in-house developed pipeline, we have now integrated information on 825,814 chemical compounds, enriched in drugs and drug-like molecules. Bioactive compounds obtained from the ChEMBL database (439,984) have information on their activity (IC50s, MICs, % inhibition etc.), their targets, and references to the literature. Using the OrthoMCL database of orthologous proteins, we have identified 4,338 pathogen proteins that share the same ortholog group with at least one druggable target in ChEMBL. These proteins could be transitively linked to 173,416 chemical compounds. Analyzing the available information on compounds, targets and activities, and their relationships, we expect to find rules that allow us to predict associations between compounds and targets; to find new molecules with some effect on pathogen targets; and to find new targets that are important in pathogen pathways and therefore potentially useful to find new drugs. As a first step, we are analyzing groups of orthologs that contain pathogen genes without any associated chemical information, but whose non-pathogen members carry information on compounds that have significant activity as inhibitors. This procedure could be useful to identify known compounds that could be tested on pathogens. Additional chemical leads (chemical analogs) can then be identified by chemical similarity searches. Preliminary results, taking into account only four assays (measurement of EC50, IC50, Minimum Inhibitory Concentration (MIC) and Ki), allowed us to identify ~7000 chemicalcompounds with activity against non-pathogen targets for 17 ortholog groups that carry essential genetic phenotypes, that could be potentially active against its ortholog pathogen genes. Supported 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).