title: A structure-based approach for mapping adverse drug reactions to the perturbation of underlying biological pathways.
abstract: Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug's ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature.
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. izharw@cs.toronto.edu
authors.forename: Izhar
authors.initials: I
authors.lastname: Wallach
authors.forename: Navdeep
authors.initials: N
authors.lastname: Jaitly
authors.forename: Ryan
authors.initials: R
authors.lastname: Lilien
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D019295:Computational Biology; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006025:Glycosaminoglycans / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006547:Hernia / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D009525:Niacin / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D006025:Glycosaminoglycans; D053823:Hedgehog Proteins; D009536:Niacinamide; D009525:Niacin; D019289:Pyruvic Acid
references.citation: J Biol Chem. 2004 Sep 17;279(38):39798-806
references.pmid: 15234978
references.citation: J Mol Graph Model. 2007 Jul;26(1):198-212
references.pmid: 16860582
references.citation: Nat Protoc. 2007;2(10):2366-82
references.pmid: 17947979
references.citation: PLoS Comput Biol. 2009 May;5(5):e1000387
references.pmid: 19436720
references.citation: J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):368-76
references.pmid: 18344392
references.citation: ChemMedChem. 2007 Dec;2(12):1774-82
references.pmid: 17952882
references.citation: J Chem Inf Model. 2009 Feb;49(2):308-17
references.pmid: 19434832
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6
references.pmid: 18048412
references.citation: Drug Discov Today. 2005 Nov 1;10(21):1421-33
references.pmid: 16243262
references.citation: PLoS Comput Biol. 2009 Jul;5(7):e1000441
references.pmid: 19629158
references.citation: J Biol Chem. 1962 Dec;237:3829-31
references.pmid: 13959778
references.citation: Nature. 2009 Nov 12;462(7270):175-81
references.pmid: 19881490
references.citation: FEMS Microbiol Lett. 1999 May 15;174(2):247-50
references.pmid: 10339815
references.citation: Hum Mol Genet. 2002 Jun 1;11(12):1399-407
references.pmid: 12023982
references.citation: Cancer Lett. 2006 Aug 18;240(1):1-8
references.pmid: 16171943
references.citation: Biomaterials. 2002 Sep;23(17):3661-71
references.pmid: 12109692
references.citation: Nat Biotechnol. 2007 Feb;25(2):197-206
references.pmid: 17287757
references.citation: Connect Tissue Res. 1982;9(3):173-9
references.pmid: 6213370
references.citation: Am J Gastroenterol. 2006 Oct;101(10):2379-400
references.pmid: 17032204
references.citation: J Am Coll Surg. 2009 Sep;209(3):371-6
references.pmid: 19717042
references.citation: J Am Acad Orthop Surg. 2007 Apr;15(4):208-17
references.pmid: 17426292
references.citation: J Gastroenterol Hepatol. 1997 Jun;12(6):437-44
references.pmid: 9195401
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Pathol Res Pract. 2002;198(10):701-7
references.pmid: 12498227
references.citation: Mol Microbiol. 2002 Mar;43(6):1379-86
references.pmid: 11971262
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D355-60
references.pmid: 19880382
references.citation: J Biomed Sci. 2009 Jul 13;16:63
references.pmid: 19594911
references.citation: Int J Urol. 2009 Oct;16(10):848-51
references.pmid: 19811549
references.citation: J Biol Chem. 2009 Aug 21;284(34):22888-97
references.pmid: 19556240
references.citation: J Pharmacol Exp Ther. 1996 May;277(2):1152-7
references.pmid: 8627527
references.citation: Science. 2008 Jul 11;321(5886):263-6
references.pmid: 18621671
references.citation: J Med Chem. 2009 May 14;52(9):3103-7
references.pmid: 19378990
references.citation: J Chem Inf Model. 2006 May-Jun;46(3):991-8
references.pmid: 16711717
references.citation: J Biol Chem. 1999 Feb 26;274(9):5810-22
references.pmid: 10026203
references.citation: Acta Diabetol. 1999 Jun;36(1-2):35-8
references.pmid: 10436250
references.citation: Best Pract Res Clin Rheumatol. 2001 Jul;15(3):401-13
references.pmid: 11485337
references.citation: J Clin Invest. 2005 Feb;115(2):209-18
references.pmid: 15690074
references.citation: Nat Rev Drug Discov. 2005 May;4(5):410-20
references.pmid: 15864270
references.citation: PLoS Genet. 2008 Aug 08;4(8):e1000151
references.pmid: 18688276
references.citation: J Virol. 2006 Nov;80(21):10325-34
references.pmid: 17041213
references.citation: Genome Inform. 2004;15(2):31-41
references.pmid: 15706489
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):353-9
references.pmid: 15060530
references.citation: Diabetes Care. 2000 Apr;23(4):564-5
references.pmid: 10857958
references.citation: Nat Rev Drug Discov. 2006 Dec;5(12):993-6
references.pmid: 17139284
references.citation: PLoS Comput Biol. 2010 Jan 22;6(1):e1000648
references.pmid: 20098496
references.citation: Nat Chem Biol. 2005 Dec;1(7):389-97
references.pmid: 16370374
references.citation: J Med Chem. 2009 Sep 24;52(18):5712-20
references.pmid: 19719084
references.citation: N Engl J Med. 2003 Feb 6;348(6):538-49
references.pmid: 12571262
references.citation: Mol Syst Biol. 2010;6:343
references.pmid: 20087340
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5895-900
references.pmid: 17392427
references.citation: Nat Clin Pract Rheumatol. 2006 Jan;2(1):35-43
references.pmid: 16932650
references.citation: Cancer Res. 2003 May 15;63(10):2440-6
references.pmid: 12750264
references.citation: Bioinformatics. 2009 Mar 15;25(6):714-21
references.pmid: 19176549
references.citation: J Med Chem. 2006 Nov 16;49(23):6789-801
references.pmid: 17154509
references.citation: Scand J Gastroenterol. 2009;44(5):626-32
references.pmid: 19194821
references.citation: J Med Microbiol. 1999 Mar;48(3):223-233
references.pmid: 10334589
references.citation: BMC Struct Biol. 2006 Sep 24;6:19
references.pmid: 16995956