title: Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.
abstract: BACKGROUND
  The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni.
  
  
  RESULTS
  Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets.
  
  
  CONCLUSIONS
  Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates that may merit further study, the lists can easily be modified in a user-specific manner, either by adjusting the weights for chosen criteria or by changing the criteria that are included.
authors.affiliation: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, United States of America. crowther@u.washington.edu
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Crowther
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Shanmugam
authors.forename: Santiago J
authors.initials: SJ
authors.lastname: Carmona
authors.forename: Maria A
authors.initials: MA
authors.lastname: Doyle
authors.forename: Christiane
authors.initials: C
authors.lastname: Hertz-Fowler
authors.forename: Matthew
authors.initials: M
authors.lastname: Berriman
authors.forename: Solomon
authors.initials: S
authors.lastname: Nwaka
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Ralph
authors.forename: David S
authors.initials: DS
authors.lastname: Roos
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Fernán
authors.initials: F
authors.lastname: Agüero
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D015801:Helminth Proteins; D015800:Protozoan Proteins
references.citation: Invert Neurosci. 2007 Dec;7(4):199-208
references.pmid: 17962986
references.citation: Science. 2005 Jul 15;309(5733):473-6
references.pmid: 16020736
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D579-82
references.pmid: 18842636
references.citation: Am J Physiol. 1989 Sep;257(3 Pt 2):R618-25
references.pmid: 2782464
references.citation: Mol Syst Biol. 2008;4:177
references.pmid: 18364711
references.citation: BMC Genomics. 2010 Apr 03;11:222
references.pmid: 20361874
references.citation: Cell Microbiol. 2009 Mar;11(3):506-20
references.pmid: 19068099
references.citation: Comput Biol Chem. 2005 Oct;29(5):368-78
references.pmid: 16213791
references.citation: Nat Rev Drug Discov. 2002 Sep;1(9):727-30
references.pmid: 12209152
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):305-10
references.pmid: 18172196
references.citation: J Biol Chem. 2005 Aug 5;280(31):28306-15
references.pmid: 15955817
references.citation: PLoS Comput Biol. 2006 Jun 9;2(6):e61
references.pmid: 16789813
references.citation: Genomics. 2007 Jan;89(1):36-43
references.pmid: 17070005
references.citation: IUBMB Life. 2009 Nov;61(11):1083-91
references.pmid: 19859979
references.citation: Mol Microbiol. 2003 Apr;48(1):77-84
references.pmid: 12657046
references.citation: PLoS Negl Trop Dis. 2010 Apr 13;4(4):e659
references.pmid: 20405000
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D302-5
references.pmid: 16381872
references.citation: Mini Rev Med Chem. 2006 Feb;6(2):177-202
references.pmid: 16472186
references.citation: BMC Infect Dis. 2007 Jul 26;7:84
references.pmid: 17655757
references.citation: Mol Biochem Parasitol. 2010 Jan;169(1):50-4
references.pmid: 19748525
references.citation: Chem Biol Drug Des. 2010 Jan;75(1):115-26
references.pmid: 19895504
references.citation: J Biol Chem. 1997 Aug 1;272(31):19488-96
references.pmid: 9235951
references.citation: In Silico Biol. 2004;4(3):355-60
references.pmid: 15724285
references.citation: PLoS One. 2007 Apr 18;2(4):e383
references.pmid: 17440619
references.citation: Mol Biochem Parasitol. 2006 Aug;148(2):144-60
references.pmid: 16644028
references.citation: Curr Drug Targets. 2007 Jan;8(1):49-60
references.pmid: 17266530
references.citation: Traffic. 2008 Feb;9(2):166-75
references.pmid: 17900270
references.citation: Vet J. 1997 Jul;154(1):11-34
references.pmid: 9265850
references.citation: Science. 2003 Sep 12;301(5639):1503-8
references.pmid: 12893887
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D588-92
references.pmid: 18984617
references.citation: Biochem J. 2009 May 27;420(3):451-62
references.pmid: 19296828
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12989-94
references.pmid: 14569030
references.citation: Int J Parasitol. 2008 Feb;38(2):137-41
references.pmid: 17991467
references.citation: Mol Biochem Parasitol. 1998 Mar 1;91(1):37-49
references.pmid: 9574924
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D457-62
references.pmid: 19843604
references.citation: BMC Syst Biol. 2008 Dec 19;2:109
references.pmid: 19099550
references.citation: PLoS One. 2009;4(2):e4413
references.pmid: 19198654
references.citation: J Mol Graph Model. 2004 Dec;23(3):275-84
references.pmid: 15530823
references.citation: J Mol Biol. 2010 Mar 26;397(2):481-94
references.pmid: 20132829
references.citation: Nat Rev Drug Discov. 2006 Nov;5(11):941-55
references.pmid: 17080030
references.citation: J Comput Aided Mol Des. 2009 Apr;23(4):195-8
references.pmid: 19194660
references.citation: Trends Genet. 2004 Nov;20(11):544-9
references.pmid: 15475113
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D539-43
references.pmid: 18957442
references.citation: Annu Rev Microbiol. 2000;54:129-56
references.pmid: 11018126
references.citation: Parasitology. 1981 Feb;82(1):97-109
references.pmid: 7208106
references.citation: Proteins. 2001 Nov 1;45(2):136-43
references.pmid: 11562943
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8327-32
references.pmid: 15928073
references.citation: J Mol Biol. 2009 Oct 23;393(2):504-13
references.pmid: 19695264
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4865-70
references.pmid: 15024109
references.citation: Mol Biochem Parasitol. 2007 Dec;156(2):235-45
references.pmid: 17904661
references.citation: Protein Expr Purif. 2003 Apr;28(2):287-92
references.pmid: 12699693
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D555-9
references.pmid: 18948289
references.citation: Methods Mol Biol. 2008;416:45-59
references.pmid: 18392960
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D347-54
references.pmid: 18948282
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7213-8
references.pmid: 12775759
references.citation: PLoS One. 2007 Nov 14;2(11):e1189
references.pmid: 18000556
references.citation: Nat Rev Drug Discov. 2008 Nov;7(11):900-7
references.pmid: 18927591
references.citation: Nature. 2009 Jul 16;460(7253):352-8
references.pmid: 19606141
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D363-8
references.pmid: 16381887
references.citation: Chem Biol Drug Des. 2008 Nov;72(5):444-9
references.pmid: 19012578
references.citation: Science. 2003 Jan 31;299(5607):705-8
references.pmid: 12560551