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TDRtargets.org: an open-access resource for prioritizing possible drug targets and linking them to possible inhibitors
1. TDRtargets.org : an open-access resource for prioritizing possible drug targets and linking them to possible inhibitors Gregory J. Crowther 1 and Fernán Agüero 2 with Santiago J. Carmona 2 , M. Paula Magari ñ os 2 , Dhanasekaran Shanmugam 3 , Maria A. Doyle 4 , Christiane Hertz-Fowler 5 , Matthew Berriman 5 , Solomon Nwaka 6 , Stuart A. Ralph 4 , David S. Roos 3 , John P. Overington 7 , and Wesley C. Van Voorhis 1 1 University of Washington , 2 Universidad de San Martín , 3 University of Pennsylvania , 4 University of Melbourne , 5 Wellcome Trust Sanger Institute , 6 TDR / World Health Organization, and 7 European Bioinformatics Institute 1100101101010001001011011110110011001101011001001110110110001101010110010110001010010101
2. Overview of TDRtargets.org • Established in 2007 with funding from TDR division of World Health Organization • Open-access database to facilitate target -based drug development for “neglected diseases” • More details: F. Agüero et al., Nat. Rev. Drug Discov. 7 : 900-7, 2008 Disease Reference Pathogen African sleeping sickness Trypanosoma brucei Chagas disease Trypanosoma cruzi Filariasis Brugia malayi Leishmaniasis Leishmania major Leprosy Mycobacterium leprae Malaria Plasmodium falciparum , P. vivax Schistosomiasis Schistosoma mansoni Toxoplasmosis Toxoplasma gondii Tuberculosis Mycobacterium tuberculosis
3. home | targets | compounds | history | posted lists | targets survey | manual | My Queries: 0 Login | Register | Documentation | Contact | FAQ SEARCH FOR TARGETS SEARCH FOR COMPOUNDS BROWSE PUBLIC LISTS OF TARGETS SAVE YOUR SEARCHES
4. Target-based drug development Identify possible drug targets (proteins). Express and purify targets. Solve targets’ 3D structures with bound compounds. Confirm that compounds kill cells via the associated targets. Preclinical (animal) testing: efficacy, ADME, toxicity. Screen for compound-target associations. Optimize compounds for selective inhibition. TDRtargets.org
5. Overview of TDRtargets.org • Original goal: facilitate identification of proteins with traits of good drug targets. Sample Criterion Weight Criterion met by Protein X? Assayable 20 Yes Crystallizable 10 No Druggable 30 Yes Essential 25 Yes predicted from protein binding pockets and similarities to known drug targets (A. Hopkins, B. Al-Lazikani, J. Overington) orthology is used to make inferences about incompletely studied proteins (D. Roos) according to sigma.com and brenda-enzymes.org according to Protein Data Bank (pdb.org)
6. Weighting allows proteins to be ranked based on many criteria without discarding those that lack some desired criteria; e.g., 1. Protein Y (75 points) 2. Protein Z (45 points) 3. Protein X (30 points) Overview of TDRtargets.org • Original goal: facilitate identification of proteins with traits of good drug targets. Sample Criterion Weight Protein X Protein Y Protein Z Assayable 20 Yes Yes Yes Crystallizable 10 Yes No No Druggable 30 No Yes No Essential 25 No Yes Yes
9. Examples of prioritizing targets “ Identification of attractive drug targets in neglected-disease pathogens using an in silico approach” (G. J. Crowther et al., PLoS Negl. Trop. Dis. 4 : e804, 2010) • made good lists of promising drug targets in several species (http://www.tdrtargets.org/published/browse/366) • compared to lists previously published by others • explored plusses and minuses of bioinformatics-based rankings
10. Figure 2 : A summary of the multiparameter search queries presented in this study.
11. Criteria for Table 6 ( T. brucei glycolysis) User-uploaded list Criterion Weight is a protein 1 has associated PubMed publications 20 has a solved crystal structure 20 has a ModBase 3D model 10 has a druggability index ≥ 0.4 20 has a compound desirability index > 0.2 10 has a precedent for assayability 20 classified by KEGG as a glycolytic/gluconeogenic enzyme 1000 glycolytic flux control (based on M. A. Albert et al., 2005) glyceraldehyde-3-phosphate dehydrogenase (1.2.1.12) glycerol-3-phosphate dehydrogenase (1.1.1.8) glycerol-3-phosphate oxidase (1.1.99.5) phosphoglycerate mutase (5.4.2.1) aldolase (4.1.2.13) enolase (4.2.1.11) phosphoglycerate kinase (2.7.2.3) pyruvate kinase (2.7.1.40) 40 30 30 30 10 10 10 10
22. What would make TDRtargets.org even more useful and popular? • More screening data (e.g., for M. tuberculosis )? • Additional ways to link compounds and targets? • Additional datasets (e.g., transcriptomics) for prioritizing targets, and better user interface via closer alignment with EuPathDB.org? • Other ideas? 2° association . . . Upgrade to 1°?
23. Summary • TDRtargets.org is an open-access database that facilitates target-based drug development for neglected diseases. • Targets may be prioritized with weighted searches of multiple criteria. • The main goal of the website is NOT to establish “canonical” top-10 lists, but to let visitors use their own criteria to find targets that are attractive to them. • A focus of ongoing work is the use of curation and informatics to link compounds and targets.