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Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease.

Arvind K Chavali | Anna S Blazier | Jose L Tlaxca | Paul A Jensen | Richard D Pearson | Jason A Papin
BMC systems biology | 2012

Systems biology holds promise as a new approach to drug target identification and drug discovery against neglected tropical diseases. Genome-scale metabolic reconstructions, assembled from annotated genomes and a vast array of bioinformatics/biochemical resources, provide a framework for the interrogation of human pathogens and serve as a platform for generation of future experimental hypotheses. In this article, with the application of selection criteria for both Leishmania major targets (e.g. in silico gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low-toxic Food and Drug Administration (FDA)-approved drugs is introduced.

Pubmed ID: 22540944

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: GM088244

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This is a list of tools and resources that we have found mentioned in this publication.


DrugBank (tool)

RRID:SCR_002700

Bioinformatics and cheminformatics database that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.

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GeneDB Lmajor (tool)

RRID:SCR_004613

Database of the most recent sequence updates and annotations for the L. major genome. New annotations are constantly being added to keep up with published manuscripts and feedback from the Trypanosomatid research community. You may search by Protein Length, Molecular Mass, Gene Type, Date, Location, Protein Targeting, Transmembrane Helices, Product, GO, EC, Pfam ID, Curation and Comments, and Dbxrefs. BLAST and other tools are available. Leishmania species cause a spectrum of human diseases in tropical and subtropical regions of the world. We have sequenced the 36 chromosomes of the 32.8-megabase haploid genome of Leishmania major (Friedlin strain) and predict 911 RNA genes, 39 pseudogenes, and 8272 protein-coding genes, of which 36% can be ascribed a putative function. These include genes involved in host-pathogen interactions, such as proteolytic enzymes, and extensive machinery for synthesis of complex surface glycoconjugates. The Pathogen Genomics group at the Wellcome Trust Sanger Institute played a major role in sequencing the genome of Leishmania major (see Ivens et al.) Details of the centres involved and which chromosomes they sequenced, are given. The sequence data were obtained by adopting several parallel approaches, including complete cosmid sequencing, whole chromosome shotguns and/or BAC sequencing/skimming. The Leishmania parasite is an intracellular pathogen of the immune system targeting macrophages and dendritic cells. The disease Leishmaniasis affects the populations of 88 counties worldwide with symptoms ranging from disfiguring cutaneous and muco-cutaneous lesions that can cause widespread destruction of mucous membranes to visceral disease affecting the haemopoetic organs. In collaboration with GeneDB, the EuPathDB genomic sequence data and annotations are regularly deposited on TriTrypDB where they can be integrated with other datasets and queried using customized queries.

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STRING (tool)

RRID:SCR_005223

Database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations and are derived from four sources: Genomic Context, High-throughput experiments, (Conserved) Coexpression, and previous knowledge. STRING quantitatively integrates interaction data from these sources for a large number of organisms, and transfers information between these organisms where applicable. The database currently covers 5''214''234 proteins from 1133 organisms. (2013)

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NCBI (tool)

RRID:SCR_006472

A portal to biomedical and genomic information. NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease.

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Search Tool for Interactions of Chemicals (tool)

RRID:SCR_007947

Database to explore known and predicted interactions of chemicals and proteins. It integrates information about interactions from metabolic pathways, crystal structures, binding experiments and drug-target relationships. Inferred information from phenotypic effects, text mining and chemical structure similarity is used to predict relations between chemicals. STITCH further allows exploring the network of chemical relations, also in the context of associated binding proteins. Each proposed interaction can be traced back to the original data sources. The database contains interaction information for over 68,000 different chemicals, including 2200 drugs, and connects them to 1.5 million genes across 373 genomes and their interactions contained in the STRING database.

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TDR Targets Database (tool)

RRID:SCR_007963

This database functions both as a website where researchers can look for information on their targets of interest; and as a tool for prioritization of targets in whole genomes. Using the database as a tool, researchers can quickly prioritize a genome of interest by performing any number of individual queries on a species of interest, then assigning numerical weights to each query (in the history page) to finally obtain a ranked list of genes by combining the weighted queries. This site is part of a WHO/TDR project seeking to exploit the availability of diverse datasets to facilitate the identification and prioritization of drug targets in pathogens causing neglected diseases.

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Thermo Fisher Scientific (tool)

RRID:SCR_008452

Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.

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Molecular Probes (tool)

RRID:SCR_013318

An Antibody supplier and subset of ThermoFisher Scientific which provides fluorescence reagents for various experiments and methods.

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COBrA (tool)

RRID:SCR_005677

COBrA is a Java-based ontology editor for bio-ontologies that distinguishes itself from other editors by supporting the linking of concepts between two ontologies, and providing sophisticated analysis and verification functions. In addition to the Gene Ontology and Open Biology Ontologies formats, COBrA can import and export ontologies in the Semantic Web formats RDF, RDFS and OWL. Platform: Windows compatible, Mac OS X compatible, Linux compatible, Unix compatible

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