Journal of Computer-Aided Molecular Design

, Volume 26, Issue 11, pp 1247–1266 | Cite as

Ligand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A1, A2A, A2B, and A3 receptor antagonists

  • Francesco Sirci
  • Laura Goracci
  • David Rodríguez
  • Jacqueline van Muijlwijk-Koezen
  • Hugo Gutiérrez-de-Terán
  • Raimund Mannhold
Article

Abstract

FLAP fingerprints are applied in the ligand-, structure- and pharmacophore-based mode in a case study on antagonists of all four adenosine receptor (AR) subtypes. Structurally diverse antagonist collections with respect to the different ARs were constructed by including binding data to human species only. FLAP models well discriminate “active” (=highly potent) from “inactive” (=weakly potent) AR antagonists, as indicated by enrichment curves, numbers of false positives, and AUC values. For all FLAP modes, model predictivity slightly decreases as follows: A2BR > A2AR > A3R > A1R antagonists. General performance of FLAP modes in this study is: ligand- > structure- > pharmacophore- based mode. We also compared the FLAP performance with other common ligand- and structure-based fingerprints. Concerning the ligand-based mode, FLAP model performance is superior to ECFP4 and ROCS for all AR subtypes. Although focusing on the early first part of the A2A, A2B and A3 enrichment curves, ECFP4 and ROCS still retain a satisfactory retrieval of actives. FLAP is also superior when comparing the structure-based mode with PLANTS and GOLD. In this study we applied for the first time the novel FLAPPharm tool for pharmacophore generation. Pharmacophore hypotheses, generated with this tool, convincingly match with formerly published data. Finally, we could demonstrate the capability of FLAP models to uncover selectivity aspects although single AR subtype models were not trained for this purpose.

Keywords

Adenosine receptor subtypes FLAP G protein coupled receptors (GPCRs) GOLD GRID PLANTS ECFP4 ROCS Ligand-based virtual screening Structure-based virtual screening Pharmacophore-based virtual screening 

Abbreviations

AR

Adenosine receptors

AUC

Area under the curve

ECFP4

Extended-connectivity fingeprint

EF

Enrichment factor

FLAP

Fingerprint of ligands and proteins

FN

False negative(s)

FP

False positive(s)

GOLD

Genetic optimization of ligand docking H-bonding, hydrogen bonding

LDA

Linear discriminant analysis

MIF

Molecular interaction fields

PLANTS

Protein-ligand ant colony optimization

QSAR

Quantitative structure–activity relationships

ROC

Receiver operating characteristic

ROCS

Rapid overlay of chemical structures

Supplementary material

10822_2012_9612_MOESM1_ESM.xls (274 kb)
Supplementary material 1 (XLS 274 kb)
10822_2012_9612_MOESM2_ESM.doc (428 kb)
Supplementary material 2 (DOC 427 kb)

References

  1. 1.
    Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J (2001) Pharmacol Rev 53(4):527Google Scholar
  2. 2.
    Zhou QY, Li CY, Olah ME, Johnson RA, Stiles GL, Civelli O (1992) Proc Nat Acad Sci USA 89(16):7432CrossRefGoogle Scholar
  3. 3.
    Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG (1993) Proc Nat Acad Sci USA 90(21):10365CrossRefGoogle Scholar
  4. 4.
    Ralevic V, Burnstock G (1998) Pharmacol Rev 50(3):413Google Scholar
  5. 5.
    Fredholm BB (2011) Sleep Biol Rhythms 9:24CrossRefGoogle Scholar
  6. 6.
    Gessi S, Merighi S, Varani K, Borea PA (2011) Advances in pharmacology (San Diego, Calif) 61:41Google Scholar
  7. 7.
    Mueller CE, Jacobson KA (2011) Biochimica Et Biophysica Acta-Biomembranes 1808(5):1290CrossRefGoogle Scholar
  8. 8.
    Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Mueller CE (2011) Pharmacol Rev 63(1):1CrossRefGoogle Scholar
  9. 9.
    Langmead CJ, Andrews SP, Congreve M, Errey JC, Hurrell E, Marshall FH, Mason JS, Richardson CM, Robertson N, Zhukov A, Weir M (2012) J Med Chem 55(5):1904CrossRefGoogle Scholar
  10. 10.
    Martinelli A, Tuccinardi T (2007) Med Res Rev 28(2):247Google Scholar
  11. 11.
    Michielan L, Stephanie F, Terfloth L, Hristozov D, Cacciari B, Klotz K-N, Spalluto G, Gasteiger J, Moro S (2009) J Chem Inf Model 49(12):2820CrossRefGoogle Scholar
  12. 12.
    Costanzi S, Tikhonova IG, Harden TK, Jacobson KA (2009) J Comput Aided Mol Des 23(11):747CrossRefGoogle Scholar
  13. 13.
    Goddard WA III, Kim S-K, Li Y, Trzaskowski B, Griffith AR, Abrol R (2010) J Struct Biol 170(1):10CrossRefGoogle Scholar
  14. 14.
    Wei J, Wang S, Gao S, Dai X, Gao Q (2007) J Chem Inf Model 47(2):613CrossRefGoogle Scholar
  15. 15.
    Tafi A, Bernardini C, Botta M, Corelli F, Andreini M, Martinelli A, Ortore G, Baraldi PG, Fruttarolo F, Borea PA, Tuccinardi T (2006) J Med Chem 49(14):4085CrossRefGoogle Scholar
  16. 16.
    Cheong SL, Federico S, Venkatesan G, Paira P, Shao Y-M, Spalluto G, Yap CW, Pastorin G (2011) Bioorg Med Chem Lett 21(10):2898CrossRefGoogle Scholar
  17. 17.
    Xu Z, Cheng F, Da C, Liu G, Tang Y (2010) J Mol Model 16(12):1867CrossRefGoogle Scholar
  18. 18.
    Cheng F, Xu Z, Liu G, Tang Y (2010) Eur J Med Chem 45(8):3459CrossRefGoogle Scholar
  19. 19.
    Wei J, Li H, Qu W, Gao Q (2009) Neurochem Int 55(7):637CrossRefGoogle Scholar
  20. 20.
    Yaziji V, Rodriguez D, Gutierrez-de-Teran H, Coelho A, Caamano O, Garcia-Mera X, Brea J, Isabel Loza M, Isabel Cadavid M, Sotelo E (2011) J Med Chem 54(2):457Google Scholar
  21. 21.
    Faller B, Ottaviani G, Ertl P, Berellini G, Collis A (2011) Drug Discov Today 16(21–22):976CrossRefGoogle Scholar
  22. 22.
    Baroni M, Cruciani G, Sciabola S, Perruccio F, Mason JS (2007) J Chem Inf Model 47(2):279CrossRefGoogle Scholar
  23. 23.
    Cross S, Baroni M, Carosati E, Benedetti P, Clementi S (2010) J Chem Inf Model 50(8):1442CrossRefGoogle Scholar
  24. 24.
    Grant JA, Gallardo MA, Pickup BT (1996) J Comput Chem 17(14):1653CrossRefGoogle Scholar
  25. 25.
    Rogers D, Hahn M (2010) J Chem Inf Model 50(5):742CrossRefGoogle Scholar
  26. 26.
    Korb OS, Exner TE (2007) Swarm Intell 1:115Google Scholar
  27. 27.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727CrossRefGoogle Scholar
  28. 28.
  29. 29.
    Gasteiger J, Teckentrup A, Terfloth L, Spycher S (2003) J Phys Org Chem 16(4):232CrossRefGoogle Scholar
  30. 30.
    Milletti F, Storchi L, Sforna G, Cruciani G (2007) J Chem Inf Model 47:2172CrossRefGoogle Scholar
  31. 31.
    Cruciani C, Crivori P, Carrupt PA, Testa B (2000) J Mol Struct Theochem 503(1–2):17CrossRefGoogle Scholar
  32. 32.
    Cruciani G, Pastor M, Guba W (2000) Eur J Pharm Sci 11:S29CrossRefGoogle Scholar
  33. 33.
    Hudson BD, Hyde RM, Rahr E, Wood J (1996) Quant Struct-Act Relat 15(4):285CrossRefGoogle Scholar
  34. 34.
    Carosati E, Sciabola S, Cruciani G (2004) J Med Chem 47(21):5114CrossRefGoogle Scholar
  35. 35.
    Brincat JP, Carosati E, Sabatini S, Manfroni G, Fravolini A, Raygada JL, Pate D, Kaatz GW, Cruciani G (2011) J Med Chem 54(1):354CrossRefGoogle Scholar
  36. 36.
    Carosati E, Mannhold R, Wahl P, Hansen JB, Fremming T, Zamora I, Cianchetta G, Baroni M (2007) J Med Chem 50(9):2117CrossRefGoogle Scholar
  37. 37.
    Sciabola S, Stanton RV, Mills JE, Flocco MM, Baroni M, Cruciani G, Perruccio F, Mason JS (2010) J Chem Inf Model 50:155CrossRefGoogle Scholar
  38. 38.
    Cross S, Baroni M, Goracci L, Cruciani G (2012) J Chem Inf Model 21:21Google Scholar
  39. 39.
    Cross S, Ortuso F, Baroni M, Costa G, Distinto S, Moraca F, Alcaro S, Cruciani G (2012) J Chem Inf Model 21:21Google Scholar
  40. 40.
    Bostrom J, Greenwood JR, Gottfries J (2003) J Mol Graph Model 21(5):449CrossRefGoogle Scholar
  41. 41.
  42. 42.
    Morgan HL (1965) J Chem Doc 5(2):107CrossRefGoogle Scholar
  43. 43.
    Jaakola V-P, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, Ijzerman AP, Stevens RC (2008) Science 322(5905):1211CrossRefGoogle Scholar
  44. 44.
    Rodriguez D, Pineiro A, Gutierrez-de-Teran H (2011) Biochemistry 50(19):4194CrossRefGoogle Scholar
  45. 45.
    Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) Nucleic Acids Res 25(24):4876CrossRefGoogle Scholar
  46. 46.
    Sali A, Blundell TL (1993) J Mol Biol 234(3):779CrossRefGoogle Scholar
  47. 47.
    Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) J Appl Crystallog 26:283CrossRefGoogle Scholar
  48. 48.
    Davis IW, Leaver-Fay A, Chen VB, Block JN, Kapral GJ, Wang X, Murray LW, Arendall WB, 3rd, Snoeyink J, Richardson JS, Richardson DC (2007) Nucleic Acids Res 35(Web Server issue):W375Google Scholar
  49. 49.
    Fiser A, Do RK, Sali A (2000) Protein Sci 9(9):1753CrossRefGoogle Scholar
  50. 50.
    Macromodel, version 9.7, Schrödinger L, New York, NY, 2009Google Scholar
  51. 51.
    Korb O, Stutzle T, Exner TE (2009) J Chem Inf Model 49(1):84CrossRefGoogle Scholar
  52. 52.
    Ballesteros JA, Weinstein H (1995) Methods Neurosci 25:366CrossRefGoogle Scholar
  53. 53.
    Xu F, Stevens Raymond C (2011) Structure (London, England: 1993) 19(9):1204Google Scholar
  54. 54.
    Oprea TI, Gottfries J (2001) J Comb Chem 3(2):157CrossRefGoogle Scholar
  55. 55.
    Fisher RA (1936) Ann Eugen 7:179Google Scholar
  56. 56.
    Mc Lachlan GJ (2004) Wiley series in probability and statisticsGoogle Scholar
  57. 57.
    Jacobson KA, Linden J (2011) Advances in pharmacology 61 (XV–XVI)Google Scholar
  58. 58.
    Chang LCW, Spanjersberg RF, Kunzel JKVFD, Brussee J, Ijzerman AP (2006) J Med Chem 49(10):2861CrossRefGoogle Scholar
  59. 59.
    Scheiff AB, Yerande SG, El-Tayeb A, Li W, Inamdar GS, Vasu KK, Sudarsanam V, Mueller CE (2010) Bioorg Med Chem 18(6):2195CrossRefGoogle Scholar
  60. 60.
    Ferrarini PL, Betti L, Cavallini T, Giannaccini G, Lucacchini A, Manera C, Martinelli A, Ortore G, Saccomanni G, Tuccinardi T (2004) J Med Chem 47(12):3019CrossRefGoogle Scholar
  61. 61.
    Novellino E, Cosimelli B, Ehlardo M, Greco G, Iadanza M, Lavecchia A, Rimoli MG, Sala A, Da Settimo A, Primofiore G, Da Settimo F, Taliani S, La Motta C, Klotz KN, Tuscano D, Trincavelli ML, Martini C (2005) J Med Chem 48(26):8253CrossRefGoogle Scholar
  62. 62.
    Manetti F, Schenone S, Bondavalli F, Brullo C, Bruno O, Ranise A, Mosti L, Menozzi G, Fossa P, Trincavelli ML, Martini C, Martinelli A, Tintori C, Botta M (2005) J Med Chem 48(23):7172CrossRefGoogle Scholar
  63. 63.
    Sirci F, Istyastono EP, Vischer HF, Kooistra AJ, Nijmeijer S, Kuijer M, Wijtmans M, Mannhold R, Leurs R, Esch IJPd, Graaf Cd (2012) J Chem Inf Model (submittted)Google Scholar
  64. 64.
    Kim SK, Gao ZG, Van Rompaey P, Gross AS, Chen A, Van Calenbergh S, Jacobson KA (2003) J Med Chem 46(23):4847CrossRefGoogle Scholar
  65. 65.
    Kim JH, Wess J, Schoneberg T, Jacobson KA (1995) J Biol Chem 270:13987CrossRefGoogle Scholar
  66. 66.
    Piirainen H, Ashok Y, Nanekar RT, Jaakola V-P (2011) Biochimica Et Biophysica Acta-Biomembranes 1808(5):1233CrossRefGoogle Scholar
  67. 67.
    Ivanov AA, Baskin II, Palyulin VA, Piccagli L, Baraldi PG, Zefirov NS (2005) J Med Chem 48(22):6813CrossRefGoogle Scholar
  68. 68.
    Ivanov AA, Barak D, Jacobson KA (2009) J Med Chem 52(10):3284CrossRefGoogle Scholar
  69. 69.
    Gao ZG, Chen A, Barak D, Kim SK, Muller CE, Jacobson KA (2002) J Biol Chem 277(21):19056CrossRefGoogle Scholar
  70. 70.
    Dore AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH (2011) Structure 19(9):1283CrossRefGoogle Scholar
  71. 71.
    Weyler S, Fuelle F, Diekmann M, Schumacher B, Hinz S, Klotz K-N, Mueller CE (2006) ChemMedChem 1(8):891CrossRefGoogle Scholar
  72. 72.
    Elzein E, Rao KA, Li XF, Perry T, Parkhill E, Palle V, Varkhedkar V, Gimbel A, Zeng DW, Lustig D, Leung K, Zablocki J (2006) Bioorg Med Chem Lett 16(2):302CrossRefGoogle Scholar
  73. 73.
    Kalla RV, Elzein E, Perry T, Li X, Gimbel A, Yang M, Zeng D, Zablocki J (2008) Bioorg Med Chem Lett 18(4):1397CrossRefGoogle Scholar
  74. 74.
    Baraldi PG, Tabrizi MA, Preti D, Bovero A, Romagnoli R, Fruttarolo F, Zaid NA, Moorman AR, Varani K, Gessi S, Merighi S, Borea PA (2004) J Med Chem 47(6):1434CrossRefGoogle Scholar
  75. 75.
    Baraldi PG, Tabrizi MA, Bovero A, Avitabile B, Preti D, Fruttarolo F, Romagnoli R, Varani K, Borea PA (2003) Eur J Med Chem 38(4):367CrossRefGoogle Scholar
  76. 76.
    Baraldi PG, Cacciari B, Moro S, Spalluto G, Pastorin G, Da Ros T, Klotz KN, Varani K, Gessi S, Borea PA (2002) J Med Chem 45(4):770CrossRefGoogle Scholar
  77. 77.
    Afzelius L, Raubacher F, Karlen A, Jorgensen FS, Andersson TB, Masimirembwa CM, Zamora I (2004) Drug Metab Dispos 32(11):1218Google Scholar
  78. 78.
    Hino T, Arakawa T, Iwanari H, Yurugi-Kobayashi T, Ikeda-Suno C, Nakada-Nakura Y, Kusano-Arai O, Weyand S, Shimamura T, Nomura N, Cameron AD, Kobayashi T, Hamakubo T, Iwata S, Murata T (2012) Nature 482(7384):237Google Scholar
  79. 79.
    Gao ZG, Kim SK, Biadatti T, Chen WZ, Lee K, Barak D, Kim SG, Johnson CR, Jacobson KA (2002) J Med Chem 45(20):4471CrossRefGoogle Scholar
  80. 80.
    Jacobson KA, Gao ZG, Chen AS, Barak D, Kim SA, Lee K, Link A, Van Rompaey P, van Calenbergh S, Liang BT (2001) J Med Chem 44(24):4125CrossRefGoogle Scholar
  81. 81.
    Katritch V, Kufareva I, Abagyan R (2011) Neuropharmacology 60(1):108CrossRefGoogle Scholar
  82. 82.
    Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao Z-G, Cherezov V, Stevens RC (2011) Science 332(6027):322CrossRefGoogle Scholar
  83. 83.
    Lenzi O, Colotta V, Catarzi D, Varano F, Poli D, Filacchioni G, Varani K, Vincenzi F, Borea PA, Paoletta S, Morizzo E, Moro S (2009) J Med Chem 52(23):7640CrossRefGoogle Scholar
  84. 84.
    Congreve M, Andrews SP, Doré AS, Hollenstein K, Hurrell E, Langmead CJ, Mason JS, Ng WI, Tehan B, Zhukov A, Weir M, Marshall FH (2012) J Med Chem 55:1898CrossRefGoogle Scholar
  85. 85.
    Zhang X, Rueter JK, Chen Y, Moorjani M, Lanier MC, Lin E, Gross RS, Tellew JE, Williams JP, Lechner SM, Markison S, Joswig T, Malany S, Santos M, Castro-Palomino JC, Crespo MI, Prat M, Gual S, Diaz J-L, Saunders J, Slee DH (2008) Bioorg Med Chem Lett 18(6):1778 Google Scholar
  86. 86.
    Borrmann T, Hinz S, Lertarelli DCG, Li W, Florin NC, Scheiff AB, Mueller CE (2009) J Med Chem 52(13):3994 Google Scholar
  87. 87.
    Stefanachi A, Nicolotti O, Leonetti F, Cellamare S, Campagna F, Isabel Loza M, Manuel Brea J, Mazza F, Gavuzzo E, Carotti A (2008) Bioorg Med Chem 16(22):9780Google Scholar
  88. 88.
    Kim YC, Ji XD, Jacobson KA (1996) J Med Chem 39(21):4142Google Scholar
  89. 89.
    van Muijlwijk-Koezen JE (2001) PhD thesis Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Francesco Sirci
    • 1
  • Laura Goracci
    • 1
  • David Rodríguez
    • 2
  • Jacqueline van Muijlwijk-Koezen
    • 3
  • Hugo Gutiérrez-de-Terán
    • 2
  • Raimund Mannhold
    • 4
  1. 1.Laboratory for Chemometrics and Molecular Modeling, Chemistry DepartmentUniversity of PerugiaPerugiaItaly
  2. 2.Fundación Pública Galega de Medicina Xenómica–SERGASComplejo Hospitalario Universitario de SantiagoSantiago de CompostelaSpain
  3. 3.Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact SciencesVU University AmsterdamAmsterdamThe Netherlands
  4. 4.Department of Laser Medicine, Molecular Drug Research GroupHeinrich-Heine-UniversitätDüsseldorfGermany

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