title: A mapping of drug space from the viewpoint of small molecule metabolism.
abstract: Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the "effect space" comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.
authors.affiliation: Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.
authors.forename: James Corey
authors.initials: JC
authors.lastname: Adams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keiser
authors.forename: Li
authors.initials: L
authors.lastname: Basuino
authors.forename: Henry F
authors.initials: HF
authors.lastname: Chambers
authors.forename: Deok-Sun
authors.initials: DS
authors.lastname: Lee
authors.forename: Olaf G
authors.initials: OG
authors.lastname: Wiest
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Babbitt
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D016208:Databases, Factual; D016503:Drug Delivery Systems / Q000379:methods*; D055808:Drug Discovery; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004798:Enzymes; D004364:Pharmaceutical Preparations
references.citation: Nat Rev Drug Discov. 2006 Aug;5(8):635-40
references.pmid: 16883301
references.citation: Genome Biol. 2005;6(1):R2
references.pmid: 15642094
references.citation: Mitochondrion. 2004 Jul;4(2-3):141-52
references.pmid: 16120379
references.citation: Curr Opin Biotechnol. 2007 Dec;18(6):489-96
references.pmid: 17959370
references.citation: FEBS Lett. 1996 Feb 19;380(3):219-23
references.pmid: 8601428
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D884-91
references.pmid: 17984082
references.citation: Drug Discov Today. 2006 Dec;11(23-24):1085-92
references.pmid: 17129827
references.citation: J Med Chem. 2006 May 18;49(10):2921-38
references.pmid: 16686535
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D623-31
references.pmid: 17965431
references.citation: Nat Rev Drug Discov. 2002 Sep;1(9):727-30
references.pmid: 12209152
references.citation: Curr Opin Mol Ther. 2002 Jun;4(3):224-8
references.pmid: 12139307
references.citation: Drug Discov Today. 2005 Dec;10(23-24):1675-82
references.pmid: 16376828
references.citation: Proc Natl Acad Sci U S A. 2007 May 22;104(21):8685-90
references.pmid: 17502601
references.citation: Eur J Biochem. 1994 Jul 1;223(1):1-5
references.pmid: 7957164
references.citation: Curr Drug Targets. 2007 Mar;8(3):437-44
references.pmid: 17348836
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9880-5
references.pmid: 18599447
references.citation: Curr Opin Chem Biol. 2008 Feb;12(1):66-71
references.pmid: 18258212
references.citation: Nat Biotechnol. 2007 Feb;25(2):197-206
references.pmid: 17287757
references.citation: Nature. 2004 Dec 16;432(7019):824-8
references.pmid: 15602547
references.citation: Nat Rev Drug Discov. 2007 Jan;6(1):29-40
references.pmid: 17159923
references.citation: Curr Med Chem. 2005;12(2):191-202
references.pmid: 15638735
references.citation: J Biol Chem. 1997 May 16;272(20):13380-9
references.pmid: 9148961
references.citation: Trends Pharmacol Sci. 2005 May;26(5):258-64
references.pmid: 15860373
references.citation: J Bacteriol. 2009 Jun;191(12):4015-24
references.pmid: 19376871
references.citation: Nat Rev Drug Discov. 2006 Oct;5(10):821-34
references.pmid: 17016423
references.citation: Drug Discov Today. 2006 Dec;11(23-24):1046-53
references.pmid: 17129822
references.citation: Curr Med Chem. 2005;12(19):2241-58
references.pmid: 16178783
references.citation: Biochem Pharmacol. 1999 Mar 1;57(5):567-77
references.pmid: 9952321
references.citation: Cancer Chemother Pharmacol. 2003 Jul;52 Suppl 1:S80-9
references.pmid: 12819937
references.citation: Prog Clin Biol Res. 1989;291:167-71
references.pmid: 2726840
references.citation: Biochem Pharmacol. 1989 Nov 15;38(22):4045-51
references.pmid: 2480792
references.citation: Nat Rev Drug Discov. 2007 Aug;6(8):636-49
references.pmid: 17643090
references.citation: Curr Med Chem. 2006;13(4):377-98
references.pmid: 16475929
references.citation: Curr Opin Infect Dis. 2008 Aug;21(4):372-9
references.pmid: 18594289
references.citation: Drug Discov Today. 2005 Dec;10(23-24):1607-10
references.pmid: 16376820
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: Drug Discov Today. 2007 Aug;12(15-16):622-33
references.pmid: 17706543
references.citation: Expert Opin Pharmacother. 2008 Jun;9(9):1463-79
references.pmid: 18518778
references.citation: Nat Biotechnol. 2006 Jul;24(7):805-15
references.pmid: 16841068
references.citation: Bioinformatics. 2008 Jul 1;24(13):i232-40
references.pmid: 18586719
references.citation: Lancet Infect Dis. 2008 Jul;8(7):427-34
references.pmid: 18582835
references.citation: Expert Rev Anti Infect Ther. 2008 Jun;6(3):299-307
references.pmid: 18588495
references.citation: Pharmacogenomics. 2006 Oct;7(7):1003-16
references.pmid: 17054411
references.citation: Pharmacotherapy. 2008 Feb;28(2):235-49
references.pmid: 18225969
references.citation: Expert Opin Drug Metab Toxicol. 2005 Aug;1(2):303-24
references.pmid: 16922645
references.citation: Nat Biotechnol. 2007 Jan;25(1):71-5
references.pmid: 17211405
references.citation: Curr Pharm Des. 2003;9(31):2593-613
references.pmid: 14529544
references.citation: AIDS. 2006 Mar 21;20(5):675-84
references.pmid: 16514297
references.citation: Curr Opin Chem Biol. 2004 Aug;8(4):424-31
references.pmid: 15338571
references.citation: Chem Biol. 1999 May;6(5):319-31
references.pmid: 10322126
references.citation: Pharmacol Ther. 2000 Mar;85(3):183-90
references.pmid: 10739873
references.citation: J Med Chem. 2008 Oct 9;51(19):5984-92
references.pmid: 18778048
references.citation: Nat Biotechnol. 2007 Oct;25(10):1119-26
references.pmid: 17921997
references.citation: Org Biomol Chem. 2004 Nov 21;2(22):3256-66
references.pmid: 15534703
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: J Chem Inf Comput Sci. 2002 Jul-Aug;42(4):947-55
references.pmid: 12132896
references.citation: J Nat Prod. 2005 Dec;68(12):1813-20
references.pmid: 16378385