title: An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data.
abstract: BACKGROUND
  Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the recent development of high-throughput screening (HTS) technologies. Individual PPIs have been targeted by small drug-like chemicals (SDCs), however, interactome data have not been fully utilized for exploring drug targets due to the lack of comprehensive methodology for utilizing these data. Here we propose an integrative in silico approach for discovering candidates for drug-targetable PPIs in interactome data.
  
  
  RESULTS
  Our novel in silico screening system comprises three independent assessment procedures: i) detection of protein domains responsible for PPIs, ii) finding SDC-binding pockets on protein surfaces, and iii) evaluating similarities in the assignment of Gene Ontology (GO) terms between specific partner proteins. We discovered six candidates for drug-targetable PPIs by applying our in silico approach to original human PPI data composed of 770 binary interactions produced by our HTS yeast two-hybrid (HTS-Y2H) assays. Among them, we further examined two candidates, RXRA/NRIP1 and CDK2/CDKN1A, with respect to their biological roles, PPI network around each candidate, and tertiary structures of the interacting domains.
  
  
  CONCLUSIONS
  An integrative in silico approach for discovering candidates for drug-targetable PPIs was applied to original human PPIs data. The system excludes false positive interactions and selects reliable PPIs as drug targets. Its effectiveness was demonstrated by the discovery of the six promising candidate target PPIs. Inhibition or stabilization of the two interactions may have potential therapeutic effects against human diseases.
authors: PharmaDesign, Inc,, 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan. sugaya@pharmadesign.co.jp
authors: Nobuyoshi
authors: N
authors: Sugaya
authors: Kazuyoshi
authors: K
authors: Ikeda
authors: Toshiyuki
authors: T
authors: Tashiro
authors: Shizu
authors: S
authors: Takeda
authors: Jun
authors: J
authors: Otomo
authors: Yoshiko
authors: Y
authors: Ishida
authors: Akiko
authors: A
authors: Shiratori
authors: Atsushi
authors: A
authors: Toyoda
authors: Hideki
authors: H
authors: Noguchi
authors: Tadayuki
authors: T
authors: Takeda
authors: Satoru
authors: S
authors: Kuhara
authors: Yoshiyuki
authors: Y
authors: Sakaki
authors: Takao
authors: T
authors: Iwayanagi
mesh_terms: D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping / Q000379:methods*; D017433:Protein Structure, Secondary / Q000502:physiology; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations
references: Nature. 2000 Feb 10;403(6770):623-7
references: 10688190
references: Science. 2000 Mar 17;287(5460):1960-4
references: 10720314
references: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7124-9
references: 10860979
references: Nature. 2001 Jan 11;409(6817):211-5
references: 11196647
references: Nat Cell Biol. 2001 Feb;3(2):173-82
references: 11175750
references: J Biol Chem. 2001 Mar 2;276(9):6695-702
references: 11078741
references: Bioinformatics. 2005 Feb 1;21(3):410-2
references: 15353450
references: Genome Res. 2005 Mar;15(3):376-84
references: 15710747
references: Nature. 1996 Jul 25;382(6589):325-31
references: 8684460
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Mol Endocrinol. 1998 Jun;12(6):864-81
references: 9626662
references: J Mol Biol. 1998 Jul 3;280(1):1-9
references: 9653027
references: Drug Des Discov. 1998 May;15(3):191-8
references: 9689501
references: Protein Sci. 1998 Sep;7(9):1884-97
references: 9761470
references: Curr Opin Chem Biol. 1999 Feb;3(1):112-5
references: 10021413
references: Bioessays. 1998 Dec;20(12):1020-9
references: 10048302
references: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5698-703
references: 10318947
references: J Pharmacol Exp Ther. 1999 Jun;289(3):1271-6
references: 10336516
references: J Mol Biol. 1999 Sep 10;292(1):1-9
references: 10493852
references: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12156-61
references: 10518592
references: Cell Death Differ. 2004 Dec;11 Suppl 2:S126-43
references: 15608692
references: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
references: 15608251
references: FEBS Lett. 2006 Jan 23;580(2):380-4
references: 16376878
references: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1888-93
references: 16443686
references: Bioinformatics. 2005 Apr 1;21(7):993-1001
references: 15509600
references: J Med Chem. 2005 Apr 7;48(7):2518-25
references: 15801841
references: Bioinformatics. 2005 Apr 15;21(8):1487-94
references: 15613384
references: Bioinformatics. 2005 May 15;21(10):2496-501
references: 15728113
references: Cell. 2005 Sep 23;122(6):957-68
references: 16169070
references: Drug Discov Today. 2005 Aug 15;10(16):1111-7
references: 16182196
references: Genome Biol. 2005;6(10):R89
references: 16207360
references: Nature. 2005 Oct 20;437(7062):1173-8
references: 16189514
references: Nature. 2005 Nov 3;438(7064):103-7
references: 16267556
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D247-51
references: 16381856
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D322-6
references: 16381878
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
references: 16381955
references: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4569-74
references: 11283351
references: J Am Chem Soc. 2001 Jun 20;123(24):5643-50
references: 11403595
references: J Mol Biol. 2001 Aug 24;311(4):681-92
references: 11518523
references: J Med Chem. 2001 Dec 6;44(25):4313-24
references: 11728179
references: Nature. 2002 Jan 10;415(6868):141-7
references: 11805826
references: Nature. 2002 Jan 10;415(6868):180-3
references: 11805837
references: Science. 2002 Feb 8;295(5557):1086-9
references: 11834839
references: J Biol Chem. 2002 Mar 1;277(9):7363-8
references: 11741888
references: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3830-5
references: 11891322
references: J Autoimmun. 2002 Mar;18(2):169-79
references: 11908949
references: J Med Chem. 2002 Apr 11;45(8):1543-58
references: 11931608
references: Genome Res. 2002 Oct;12(10):1540-8
references: 12368246
references: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14440-5
references: 12374846
references: Nucleic Acids Res. 2003 Jan 1;31(1):251-4
references: 12519994
references: Angew Chem Int Ed Engl. 2003 Feb 3;42(5):535-9
references: 12569483
references: Protein Sci. 2003 Apr;12(4):811-22
references: 12649439
references: J Am Chem Soc. 2003 Apr 2;125(13):3714-5
references: 12656598
references: J Mol Biol. 2003 Apr 11;327(5):919-23
references: 12662919
references: Proteomics. 2003 Apr;3(4):380-91
references: 12687606
references: Bioinformatics. 2003 May 22;19(8):923-9
references: 12761053
references: Nucleic Acids Res. 2003 Jul 1;31(13):3352-5
references: 12824325
references: J Mol Endocrinol. 2003 Aug;31(1):1-7
references: 12914520
references: Genome Res. 2003 Oct;13(10):2363-71
references: 14525934
references: Genome Res. 2003 Nov;13(11):2498-504
references: 14597658
references: Cell Cycle. 2004 Jan;3(1):35-7
references: 14657662
references: Science. 2003 Dec 5;302(5651):1727-36
references: 14605208
references: Structure. 2003 Dec;11(12):1537-46
references: 14656438
references: Cancer Cell. 2004 Jan;5(1):91-102
references: 14749129
references: Mol Cancer Res. 2004 Jan;2(1):20-8
references: 14757842
references: Science. 2004 Feb 6;303(5659):844-8
references: 14704432
references: Nat Rev Drug Discov. 2004 Apr;3(4):301-17
references: 15060526
references: Curr Opin Struct Biol. 2004 Jun;14(3):292-9
references: 15193308
references: Cell Cycle. 2004 Jun;3(6):742-6
references: 15118410
references: Curr Opin Chem Biol. 2004 Aug;8(4):442-9
references: 15288255
references: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):13-20
references: 8552589
references: Oncogene. 1996 Feb 1;12(3):595-607
references: 8637717
references: Nature. 2006 Mar 30;440(7084):631-6
references: 16429126
references: Nature. 2006 Mar 30;440(7084):637-43
references: 16554755
references: J Clin Oncol. 2006 Apr 10;24(11):1770-83
references: 16603719
references: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7036-41
references: 16636290
references: Proteins. 2006 Jul 1;64(1):60-7
references: 16568448
references: Bioinformatics. 2006 Jun 1;22(11):1335-42
references: 16522669
references: BMC Bioinformatics. 2006;7:269
references: 16725050
references: J R Soc Interface. 2006 Apr 22;3(7):215-33
references: 16849232
references: Bioinformatics. 2006 Jul 15;22(14):1794-5
references: 16672257
references: Trends Biotechnol. 2006 Oct;24(10):435-42
references: 16876893
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D193-7
references: 17142230
references: Genome Biol. 2006;7(11):R104
references: 17094802
references: Mol Syst Biol. 2007;3:89
references: 17353931
references: In Silico Biol. 2006;6(6):515-29
references: 17518762
references: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references: 10592235
references: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1506-11
references: 10677491