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PMID: 15279849 Published · ppublish English Journal Article Review

Utility of homology models in the drug discovery process.

Drug discovery today ·Vol. 9 ·No. 15 ·2004-08-01 ·Pages 659-69

Hillisch A, Pineda LF, Hilgenfeld R

Abstract

Advances in bioinformatics and protein modeling algorithms, in addition to the enormous increase in experimental protein structure information, have aided in the generation of databases that comprise homology models of a significant portion of known genomic protein sequences. Currently, 3D structure information can be generated for up to 56% of all known proteins. However, there is considerable controversy concerning the real value of homology models for drug design. This review provides an overview of the latest developments in this area and includes selected examples of successful applications of the homology modeling technique to pharmaceutically relevant questions. In addition, the strengths and limitations of the application of homology models during all phases of the drug discovery process are discussed.

MeSH Terms
Animals Computational Biology/methods Drug Design Models, Molecular Sequence Homology, Amino Acid
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Hillisch Alexander
Bayer HealthCare AG, Apratherweg 18a, D-42096 Wuppertal, Germany. alexander.hillisch@bayerhealthcare.com
Pineda Luis Felipe
Hilgenfeld Rolf
References (79)
79 references, click to expand
  1. RU486 is not an antiprogestin in the hamster.
    J Steroid Biochem. 1987 Nov;28(5):493-7 PMID: 3682817
  2. Discovery of a potent and selective protein kinase CK2 inhibitor by high-throughput docking.
    J Med Chem. 2003 Jun 19;46(13):2656-62 PMID: 12801229
  3. Molecular modelling of CYP2B6 based on homology with the CYP2C5 crystal structure: analysis of enzyme-substrate interactions.
    Drug Metabol Drug Interact. 2002;19(2):115-35 PMID: 12751910
  4. Predicting undesirable drug interactions with promiscuous proteins in silico.
    Drug Discov Today. 2004 Mar 15;9(6):276-85 PMID: 15003246
  5. Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity.
    Mol Cell. 2000 Jan;5(1):121-31 PMID: 10678174
  6. SCOP: a structural classification of proteins database for the investigation of sequences and structures.
    J Mol Biol. 1995 Apr 7;247(4):536-40 PMID: 7723011
  7. Databases for protein-ligand complexes.
    Acta Crystallogr D Biol Crystallogr. 1998 Nov 1;54(Pt 6 Pt 1):1178-82 PMID: 10089494
  8. A molecular model of CYP2D6 constructed by homology with the CYP2C5 crystallographic template: investigation of enzyme-substrate interactions.
    Drug Metabol Drug Interact. 2003;19(3):189-210 PMID: 14682610
  9. Homology modelling of CYP2A6 based on the CYP2C5 crystallographic template: enzyme-substrate interactions and QSARs for binding affinity and inhibition.
    Toxicol In Vitro. 2003 Apr;17(2):179-90 PMID: 12650672
  10. Rational discovery of novel nuclear hormone receptor antagonists.
    Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1008-13 PMID: 10655475
  11. Molecular modelling of the human glucocorticoid receptor (hGR) ligand-binding domain (LBD) by homology with the human estrogen receptor alpha (hERalpha) LBD: quantitative structure-activity relationships within a series of CYP3A4 inducers where induction is mediated via hGR involvement.
    J Steroid Biochem Mol Biol. 2002 Oct;82(2-3):195-9 PMID: 12477485
  12. The protein kinase complement of the human genome.
    Science. 2002 Dec 6;298(5600):1912-34 PMID: 12471243
  13. Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
    Bioorg Med Chem Lett. 2003 May 19;13(10):1829-35 PMID: 12729675
  14. Inhibition of the p53-hdm2 interaction with low molecular weight compounds.
    Cell Cycle. 2004 Apr;3(4):460-1 PMID: 14976429
  15. Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis.
    Mol Pharmacol. 2001 Apr;59(4):909-19 PMID: 11259637
  16. Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site.
    J Biol Chem. 2004 Mar 5;279(10):9497-503 PMID: 14676196
  17. Investigation of enzyme selectivity in the human CYP2C subfamily: homology modelling of CYP2C8, CYP2C9 and CYP2C19 from the CYP2C5 crystallographic template.
    Drug Metabol Drug Interact. 2003;19(4):257-85 PMID: 14768974
  18. A structural basis for drug-induced long QT syndrome.
    Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12329-33 PMID: 11005845
  19. MODBASE, a database of annotated comparative protein structure models, and associated resources.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D217-22 PMID: 14681398
  20. Evaluation of homology modeling of the severe acute respiratory syndrome (SARS) coronavirus main protease for structure based drug design.
    Chem Pharm Bull (Tokyo). 2004 May;52(5):643-5 PMID: 15133227
  21. Progress in protein structure prediction.
    Nat Struct Biol. 2001 Feb;8(2):110-2 PMID: 11175896
  22. Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R.
    J Pharm Belg. 1997 Mar-Apr;52(2):88-96 PMID: 9193132
  23. Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design.
    Mol Cancer Ther. 2003 Mar;2(3):283-94 PMID: 12657723
  24. Comparative protein modelling by satisfaction of spatial restraints.
    J Mol Biol. 1993 Dec 5;234(3):779-815 PMID: 8254673
  25. Assessment of homology-based predictions in CASP5.
    Proteins. 2003;53 Suppl 6:352-68 PMID: 14579324
  26. A single amino acid that determines the sensitivity of progesterone receptors to RU486.
    Science. 1992 Jan 10;255(5041):206-9 PMID: 1372753
  27. Molecular basis of P450 inhibition and activation: implications for drug development and drug therapy.
    Drug Metab Dispos. 1998 Dec;26(12):1179-84 PMID: 9860924
  28. Crystal structure of human cytochrome P450 2C9 with bound warfarin.
    Nature. 2003 Jul 24;424(6947):464-8 PMID: 12861225
  29. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor.
    J Mol Biol. 2003 Aug 22;331(4):815-28 PMID: 12909012
  30. Modern methods of drug discovery: an introduction.
    EXS. 2003;(93):1-18 PMID: 12613169
  31. Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface.
    Mol Cancer Res. 2004 Jan;2(1):20-8 PMID: 14757842
  32. Protein-based virtual screening of chemical databases. II. Are homology models of G-Protein Coupled Receptors suitable targets?
    Proteins. 2003 Jan 1;50(1):5-25 PMID: 12471595
  33. The relation between the divergence of sequence and structure in proteins.
    EMBO J. 1986 Apr;5(4):823-6 PMID: 3709526
  34. CASP5 assessment of fold recognition target predictions.
    Proteins. 2003;53 Suppl 6:395-409 PMID: 14579328
  35. Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structure-based design.
    Mol Endocrinol. 2004 Jul;18(7):1599-609 PMID: 15105439
  36. Impact of isotype-selective estrogen receptor agonists on ovarian function.
    Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5129-34 PMID: 15037755
  37. Crystal structure of rhodopsin: A G protein-coupled receptor.
    Science. 2000 Aug 4;289(5480):739-45 PMID: 10926528
  38. LigBase: a database of families of aligned ligand binding sites in known protein sequences and structures.
    Bioinformatics. 2002 Jan;18(1):200-1 PMID: 11836232
  39. Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design.
    J Med Chem. 2001 Dec 20;44(26):4615-27 PMID: 11741479
  40. Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents.
    Clin Cancer Res. 1999 Jun;5(6):1569-82 PMID: 10389946
  41. Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics.
    J Med Chem. 2003 Dec 4;46(25):5294-7 PMID: 14640538
  42. Design of helical proteins for real-time endoprotease assays.
    Anal Biochem. 2000 Nov 1;286(1):26-34 PMID: 11038269
  43. Homology modelling of human CYP1A2 based on the CYP2C5 crystallographic template structure.
    Xenobiotica. 2003 Mar;33(3):239-54 PMID: 12637242
  44. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs.
    Science. 2003 Jun 13;300(5626):1763-7 PMID: 12746549
  45. Structural classification of protein kinases using 3D molecular interaction field analysis of their ligand binding sites: target family landscapes.
    J Med Chem. 2002 Jun 6;45(12):2366-78 PMID: 12036347
  46. Use of a drug-resistant mutant of stress-activated protein kinase 2a/p38 to validate the in vivo specificity of SB 203580.
    FEBS Lett. 1999 May 21;451(2):191-6 PMID: 10371163
  47. A new method to detect related function among proteins independent of sequence and fold homology.
    J Mol Biol. 2002 Oct 18;323(2):387-406 PMID: 12381328
  48. Modeling the 3D structure of GPCRs: advances and application to drug discovery.
    Curr Opin Drug Discov Devel. 2003 May;6(3):353-61 PMID: 12833668
  49. Rational design of potent and selective EGFR tyrosine kinase inhibitors as anticancer agents.
    Curr Cancer Drug Targets. 2001 Aug;1(2):129-40 PMID: 12188886
  50. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide].
    J Biol Chem. 1999 Apr 2;274(14):9587-99 PMID: 10092645
  51. The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor.
    Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13190-5 PMID: 14585926
  52. The role of protein 3D-structures in the drug discovery process.
    EXS. 2003;(93):157-81 PMID: 12613176
  53. A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6.
    J Med Chem. 1999 Oct 7;42(20):4062-70 PMID: 10514276
  54. Drug-like properties and the causes of poor solubility and poor permeability.
    J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49 PMID: 11274893
  55. Inferring functional relationships of proteins from local sequence and spatial surface patterns.
    J Mol Biol. 2003 Sep 12;332(2):505-26 PMID: 12948498
  56. A scoring scheme for discriminating between drugs and nondrugs.
    J Med Chem. 1998 Aug 27;41(18):3325-9 PMID: 9719584
  57. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra alpha-helical domain.
    EMBO J. 2002 Jul 1;21(13):3213-24 PMID: 12093723
  58. Molecular modeling of human cytochrome P450-substrate interactions.
    Drug Metab Rev. 2002 Feb-May;34(1-2):55-67 PMID: 11996012
  59. Insights from a three-dimensional model into ligand binding to constitutive active receptor.
    Drug Metab Dispos. 2002 Sep;30(9):951-6 PMID: 12167558
  60. Establishment and functional validation of a structural homology model for human DNA methyltransferase 1.
    Biochem Biophys Res Commun. 2003 Jun 27;306(2):558-63 PMID: 12804601
  61. The druggable genome.
    Nat Rev Drug Discov. 2002 Sep;1(9):727-30 PMID: 12209152
  62. Structural bioinformatics in drug discovery.
    Methods Biochem Anal. 2003;44:477-97 PMID: 12647400
  63. PDBsum: summaries and analyses of PDB structures.
    Nucleic Acids Res. 2001 Jan 1;29(1):221-2 PMID: 11125097
  64. A 3D model of SARS_CoV 3CL proteinase and its inhibitors design by virtual screening.
    Acta Pharmacol Sin. 2003 Jun;24(6):497-504 PMID: 12791174
  65. Characterization of a novel coronavirus associated with severe acute respiratory syndrome.
    Science. 2003 May 30;300(5624):1394-9 PMID: 12730500
  66. The SWISS-MODEL Repository of annotated three-dimensional protein structure homology models.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D230-4 PMID: 14681401
  67. Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes.
    Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11000-7 PMID: 10500114
  68. Prediction of 'drug-likeness'.
    Adv Drug Deliv Rev. 2002 Mar 31;54(3):255-71 PMID: 11922947
  69. Nuclear hormone receptor targeted virtual screening.
    J Med Chem. 2003 Jul 3;46(14):3045-59 PMID: 12825943
  70. Modelling human cytochromes P450 involved in drug metabolism from the CYP2C5 crystallographic template.
    J Inorg Biochem. 2002 Sep 20;91(4):502-14 PMID: 12237218
  71. Prediction of drug metabolism: the case of cytochrome P450 2D6.
    Curr Top Med Chem. 2003;3(11):1227-39 PMID: 12769702
  72. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist.
    EMBO J. 1999 Sep 1;18(17):4608-18 PMID: 10469641
  73. Docking ligands onto binding site representations derived from proteins built by homology modelling.
    J Mol Biol. 2001 Mar 16;307(1):407-27 PMID: 11243828
  74. Transcriptional repressor CopR: structure model-based localization of the deoxyribonucleic acid binding motif.
    Proteins. 2000 Mar 1;38(4):393-406 PMID: 10707026
  75. Performance of 3D-database molecular docking studies into homology models.
    J Med Chem. 2004 Jan 29;47(3):764-7 PMID: 14736258
  76. A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity.
    Mol Cell Biol. 2002 Aug;22(15):5270-80 PMID: 12101224
  77. Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca(2+)-activated over voltage-gated K(+) channels.
    J Biol Chem. 2000 Jan 14;275(2):1201-8 PMID: 10625664
  78. Prediction of human drug metabolizing enzyme induction.
    Curr Drug Metab. 2003 Oct;4(5):381-91 PMID: 14529370
  79. Chemogenomics: an emerging strategy for rapid target and drug discovery.
    Nat Rev Genet. 2004 Apr;5(4):262-75 PMID: 15131650
Article Info
Journal
Drug discovery today
Abbr.
Drug Discov Today
ISSN
1359-6446
DOI
10.1016/S1359-6446(04)03196-4
Email
alexander.hillisch@bayerhealthcare.com
Published
2004-08-01
Pages
659-69
Language
English
Region
England
NLM ID
9604391
PMCID
PMC7129151
Subset
IM
External Links
PubMed source DOI: 10.1016/S1359-6446(04)03196-4 PMC Full Text View journal details
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