TDR Targets: a chemogenomics resource for neglected diseases.

MAGARIÑOS, MP; CARMONA SJ; CROWTHER, GJ; RALPH, SA; ROOS, DS; SHANMUGAM, D; VAN VOORHIS, WC; AGÜERO F

Foz do Iguacu

Congreso; XXVII Annual Meeting of the Brazilian Society of Protozoology; 2011

Sociedade Brasileira de Protozoologia

TDR Targets: a chemogenomics resource for neglected diseases María Paula Magariños1, Santiago J Carmona1, Gregory J Crowther2, Stuart A Ralph3, David S Roos4, Dhanasekaran Shanmugam4, Wesley Van Voorhis2 and Fernán Agüero1. 1 Instituto de Investigaciones Biotecnológicas, Universidad de San Martín, San Martín, Buenos Aires, Argentina. 2 Department of Medicine, University of Washington, Seattle, Washington, USA 3 Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, Australia 4 Department of Biology and Penn Genomics Institute, University of Pennsylvania, Philadelphia, USA The TDR Targets Database (http://tdrtargets.org) is an online resource that seeks to facilitate the prioritization of molecular targets for drug development, allowing users to numerically weight the evidence available for each gene. 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, associating them with protein targets based on manual curation of the literature. Compounds were obtained from DrugBank, PubChem and Starlite (ChEMBL) databases. A cheminformatics pipeline was developed in-house to calculate physicochemical properties and identifiers for each molecule, used to facilitate searches and cross-linking to other databases. Using this pipeline, we have now integrated 825,814 compounds. Bioactive compounds obtained from the Starlite/ChEMBL database (439,984) have information on their activity (IC50s, MICs, etc.) and their targets. Using the OrthoMCL database of orthologous proteins, we have identified 4,338 pathogen proteins that share the same ortholog group with at least one target in ChEMBL. These proteins could be transitively linked to 173,416 compounds. Using these data we are starting to define rules to propose new associations between compounds and targets. As a first step, we are analyzing groups of orthologs that contain pathogen genes without any prior chemical information, but whose non-pathogen members carry information on compounds that have significant inhibitory activity. This procedure could be useful to identify known compounds that could be tested on pathogens. Additional chemical leads can then be identified by chemical similarity. Preliminary results, taking into account only four assays (measurement of EC50, IC50, MIC and Ki), allowed us to identify new chemical leads for 17 ortholog groups that carry essential genetic phenotypes. Keywords: TDR Targets, drug discovery, neglected diseases, chemogenomics 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).