Target-Pathogen: A structural bioinformatic approach to prioritize drug targets in pathogens

SOSA, EZEQUIEL J.; BURGUENER, GERMÁN; AGUSTÍN PARDO; MARCELO MARTI; ADRIAN TURJANSKI; DARIO FERNÁNDEZ DO PORTO

Buenos Aires

Congreso; ICID 2018 / XVIII Congreso SADI; 2018

International Society for Infectious Diseases

Background: The successful use of antibiotics has been facing challenges because microbial pathogens are developing various forms of resistance. Despite this situation, new drug development projects have been inadequate for reasons ranging from bad selection of targets to reduced antimicrobial discovery efforts by pharmaceutical companies. Currently, it is accepted that identification of appropriate targets are critical steps for designing new drugs. In this sense, Next Generation Sequencing is increasingly aiding the evaluation of gene function, essentiality and suitability for drug development. Nevertheless there is a lack of online resources that allows genome wide based data consolidation define a list of potential targets. Here, we present Target-Pathogen (http://target.sbg.qb.fcen.uba.ar/patho) an online resource that facilitates the identification and prioritization of candidate targets suitable for new drug development. Methods & Materials: Target Pathogen integrates omic data, focusing on essentiality, metabolic role and structural druggability prediction of proteins. Structural information of proteins was obtained from PDB or modelled using MODELLER. For or all the structures we compute several structural properties like: DrugScore, Active site residues or PFAM relevant residues. All proteins in the database were subjected to NCBI-BLASTp and to Database of Essential Genes to asses human homology and esentiality. Metabolic networks (MN) were built by using Pathway Tools and chokepoints and topological parameters were set. Results: Target-Pathogen was designed to integrate and weigh protein information such as: function, metabolic role, off-targeting, structural properties including druggability, essentiality, and omic experiments, to facilitate the identification of candidate drug targets in pathogens. We include in the database ten genomes of some of the most relevant microorganisms for human health (Mycobacterium tuberculosis, Mycobacterium leprae, Klebsiella pneumoniae, Plasmodium vivax, Toxoplasma gondii, Leishmania major, Wolbachia bancrofti, Trypanosoma brucei, Shigella dysenteriae and Schistosoma Smanosoni) and show its applicability. New genomes can be uploaded upon request. Conclusion: The goal of Target-Pathogen is not to replace wet strategies for target identification. Rather, our goal is to become a useful resource for researchers working in the field of target identification and/or drug discovery to translate biological questions in a computational tractable way by exploring, filtering and weighting the vast quantity of genome-scale data sets.