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

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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.

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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

References

  1. Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J (2001) Pharmacol Rev 53(4):527

    CAS  Google Scholar 

  2. Zhou QY, Li CY, Olah ME, Johnson RA, Stiles GL, Civelli O (1992) Proc Nat Acad Sci USA 89(16):7432

    Article  CAS  Google Scholar 

  3. Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG (1993) Proc Nat Acad Sci USA 90(21):10365

    Article  CAS  Google Scholar 

  4. Ralevic V, Burnstock G (1998) Pharmacol Rev 50(3):413

    CAS  Google Scholar 

  5. Fredholm BB (2011) Sleep Biol Rhythms 9:24

    Article  Google Scholar 

  6. Gessi S, Merighi S, Varani K, Borea PA (2011) Advances in pharmacology (San Diego, Calif) 61:41

  7. Mueller CE, Jacobson KA (2011) Biochimica Et Biophysica Acta-Biomembranes 1808(5):1290

    Article  CAS  Google Scholar 

  8. Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Mueller CE (2011) Pharmacol Rev 63(1):1

    Article  CAS  Google Scholar 

  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):1904

    Article  CAS  Google Scholar 

  10. Martinelli A, Tuccinardi T (2007) Med Res Rev 28(2):247

    Google Scholar 

  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):2820

    Article  CAS  Google Scholar 

  12. Costanzi S, Tikhonova IG, Harden TK, Jacobson KA (2009) J Comput Aided Mol Des 23(11):747

    Article  CAS  Google Scholar 

  13. Goddard WA III, Kim S-K, Li Y, Trzaskowski B, Griffith AR, Abrol R (2010) J Struct Biol 170(1):10

    Article  CAS  Google Scholar 

  14. Wei J, Wang S, Gao S, Dai X, Gao Q (2007) J Chem Inf Model 47(2):613

    Article  CAS  Google Scholar 

  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):4085

    Article  CAS  Google Scholar 

  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):2898

    Article  CAS  Google Scholar 

  17. Xu Z, Cheng F, Da C, Liu G, Tang Y (2010) J Mol Model 16(12):1867

    Article  CAS  Google Scholar 

  18. Cheng F, Xu Z, Liu G, Tang Y (2010) Eur J Med Chem 45(8):3459

    Article  CAS  Google Scholar 

  19. Wei J, Li H, Qu W, Gao Q (2009) Neurochem Int 55(7):637

    Article  CAS  Google Scholar 

  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):457

    Google Scholar 

  21. Faller B, Ottaviani G, Ertl P, Berellini G, Collis A (2011) Drug Discov Today 16(21–22):976

    Article  CAS  Google Scholar 

  22. Baroni M, Cruciani G, Sciabola S, Perruccio F, Mason JS (2007) J Chem Inf Model 47(2):279

    Article  CAS  Google Scholar 

  23. Cross S, Baroni M, Carosati E, Benedetti P, Clementi S (2010) J Chem Inf Model 50(8):1442

    Article  CAS  Google Scholar 

  24. Grant JA, Gallardo MA, Pickup BT (1996) J Comput Chem 17(14):1653

    Article  CAS  Google Scholar 

  25. Rogers D, Hahn M (2010) J Chem Inf Model 50(5):742

    Article  CAS  Google Scholar 

  26. Korb OS, Exner TE (2007) Swarm Intell 1:115

  27. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727

    Article  CAS  Google Scholar 

  28. https://www.ebi.ac.uk/chembldb/

  29. Gasteiger J, Teckentrup A, Terfloth L, Spycher S (2003) J Phys Org Chem 16(4):232

    Article  CAS  Google Scholar 

  30. Milletti F, Storchi L, Sforna G, Cruciani G (2007) J Chem Inf Model 47:2172

    Article  CAS  Google Scholar 

  31. Cruciani C, Crivori P, Carrupt PA, Testa B (2000) J Mol Struct Theochem 503(1–2):17

    Article  CAS  Google Scholar 

  32. Cruciani G, Pastor M, Guba W (2000) Eur J Pharm Sci 11:S29

    Article  CAS  Google Scholar 

  33. Hudson BD, Hyde RM, Rahr E, Wood J (1996) Quant Struct-Act Relat 15(4):285

    Article  CAS  Google Scholar 

  34. Carosati E, Sciabola S, Cruciani G (2004) J Med Chem 47(21):5114

    Article  CAS  Google Scholar 

  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):354

    Article  CAS  Google Scholar 

  36. Carosati E, Mannhold R, Wahl P, Hansen JB, Fremming T, Zamora I, Cianchetta G, Baroni M (2007) J Med Chem 50(9):2117

    Article  CAS  Google Scholar 

  37. Sciabola S, Stanton RV, Mills JE, Flocco MM, Baroni M, Cruciani G, Perruccio F, Mason JS (2010) J Chem Inf Model 50:155

    Article  CAS  Google Scholar 

  38. Cross S, Baroni M, Goracci L, Cruciani G (2012) J Chem Inf Model 21:21

    Google Scholar 

  39. Cross S, Ortuso F, Baroni M, Costa G, Distinto S, Moraca F, Alcaro S, Cruciani G (2012) J Chem Inf Model 21:21

    Google Scholar 

  40. Bostrom J, Greenwood JR, Gottfries J (2003) J Mol Graph Model 21(5):449

    Article  CAS  Google Scholar 

  41. http://accelrys.com/products/pipeline-pilot/

  42. Morgan HL (1965) J Chem Doc 5(2):107

    Article  CAS  Google Scholar 

  43. Jaakola V-P, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, Ijzerman AP, Stevens RC (2008) Science 322(5905):1211

    Article  CAS  Google Scholar 

  44. Rodriguez D, Pineiro A, Gutierrez-de-Teran H (2011) Biochemistry 50(19):4194

    Article  CAS  Google Scholar 

  45. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) Nucleic Acids Res 25(24):4876

    Article  CAS  Google Scholar 

  46. Sali A, Blundell TL (1993) J Mol Biol 234(3):779

    Article  CAS  Google Scholar 

  47. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) J Appl Crystallog 26:283

    Article  CAS  Google Scholar 

  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):W375

  49. Fiser A, Do RK, Sali A (2000) Protein Sci 9(9):1753

    Article  CAS  Google Scholar 

  50. Macromodel, version 9.7, Schrödinger L, New York, NY, 2009

  51. Korb O, Stutzle T, Exner TE (2009) J Chem Inf Model 49(1):84

    Article  CAS  Google Scholar 

  52. Ballesteros JA, Weinstein H (1995) Methods Neurosci 25:366

    Article  CAS  Google Scholar 

  53. Xu F, Stevens Raymond C (2011) Structure (London, England: 1993) 19(9):1204

  54. Oprea TI, Gottfries J (2001) J Comb Chem 3(2):157

    Article  CAS  Google Scholar 

  55. Fisher RA (1936) Ann Eugen 7:179

    Google Scholar 

  56. Mc Lachlan GJ (2004) Wiley series in probability and statistics

  57. Jacobson KA, Linden J (2011) Advances in pharmacology 61 (XV–XVI)

  58. Chang LCW, Spanjersberg RF, Kunzel JKVFD, Brussee J, Ijzerman AP (2006) J Med Chem 49(10):2861

    Article  CAS  Google Scholar 

  59. Scheiff AB, Yerande SG, El-Tayeb A, Li W, Inamdar GS, Vasu KK, Sudarsanam V, Mueller CE (2010) Bioorg Med Chem 18(6):2195

    Article  CAS  Google Scholar 

  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):3019

    Article  CAS  Google Scholar 

  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):8253

    Article  CAS  Google Scholar 

  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):7172

    Article  CAS  Google Scholar 

  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)

  64. Kim SK, Gao ZG, Van Rompaey P, Gross AS, Chen A, Van Calenbergh S, Jacobson KA (2003) J Med Chem 46(23):4847

    Article  CAS  Google Scholar 

  65. Kim JH, Wess J, Schoneberg T, Jacobson KA (1995) J Biol Chem 270:13987

    Article  CAS  Google Scholar 

  66. Piirainen H, Ashok Y, Nanekar RT, Jaakola V-P (2011) Biochimica Et Biophysica Acta-Biomembranes 1808(5):1233

    Article  CAS  Google Scholar 

  67. Ivanov AA, Baskin II, Palyulin VA, Piccagli L, Baraldi PG, Zefirov NS (2005) J Med Chem 48(22):6813

    Article  CAS  Google Scholar 

  68. Ivanov AA, Barak D, Jacobson KA (2009) J Med Chem 52(10):3284

    Article  CAS  Google Scholar 

  69. Gao ZG, Chen A, Barak D, Kim SK, Muller CE, Jacobson KA (2002) J Biol Chem 277(21):19056

    Article  CAS  Google Scholar 

  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):1283

    Article  CAS  Google Scholar 

  71. Weyler S, Fuelle F, Diekmann M, Schumacher B, Hinz S, Klotz K-N, Mueller CE (2006) ChemMedChem 1(8):891

    Article  CAS  Google Scholar 

  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):302

    Article  CAS  Google Scholar 

  73. Kalla RV, Elzein E, Perry T, Li X, Gimbel A, Yang M, Zeng D, Zablocki J (2008) Bioorg Med Chem Lett 18(4):1397

    Article  CAS  Google Scholar 

  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):1434

    Article  CAS  Google Scholar 

  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):367

    Article  CAS  Google Scholar 

  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):770

    Article  CAS  Google Scholar 

  77. Afzelius L, Raubacher F, Karlen A, Jorgensen FS, Andersson TB, Masimirembwa CM, Zamora I (2004) Drug Metab Dispos 32(11):1218

    CAS  Google Scholar 

  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):237

    CAS  Google Scholar 

  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):4471

    Article  CAS  Google Scholar 

  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):4125

    Article  CAS  Google Scholar 

  81. Katritch V, Kufareva I, Abagyan R (2011) Neuropharmacology 60(1):108

    Article  CAS  Google Scholar 

  82. Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao Z-G, Cherezov V, Stevens RC (2011) Science 332(6027):322

    Article  CAS  Google Scholar 

  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):7640

    Article  CAS  Google Scholar 

  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 55:1898

    Article  CAS  Google Scholar 

  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. Borrmann T, Hinz S, Lertarelli DCG, Li W, Florin NC, Scheiff AB, Mueller CE (2009) J Med Chem 52(13):3994

    Google Scholar 

  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):9780

    Google Scholar 

  88. Kim YC, Ji XD, Jacobson KA (1996) J Med Chem 39(21):4142

    Google Scholar 

  89. van Muijlwijk-Koezen JE (2001) PhD thesis

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Acknowledgments

We thank Molecular Discovery Ltd. for granting FLAP suite license. We also thank Lydia Siragusa for assisting us in the Protein–Protein study.

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Authors and Affiliations

  1. Laboratory for Chemometrics and Molecular Modeling, Chemistry Department, University of Perugia, Via Elce di Sotto, 10, 06123, Perugia, Italy

    Francesco Sirci & Laura Goracci

  2. Fundación Pública Galega de Medicina Xenómica–SERGAS, Complejo Hospitalario Universitario de Santiago, A Choupana, s/n, E-15706, Santiago de Compostela, Spain

    David Rodríguez & Hugo Gutiérrez-de-Terán

  3. Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands

    Jacqueline van Muijlwijk-Koezen

  4. Department of Laser Medicine, Molecular Drug Research Group, Heinrich-Heine-Universität, Universitätsstraße 1, 40225, Düsseldorf, Germany

    Raimund Mannhold

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  1. Francesco Sirci
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  2. Laura Goracci
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  3. David Rodríguez
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  4. Jacqueline van Muijlwijk-Koezen
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  5. Hugo Gutiérrez-de-Terán
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Correspondence to Francesco Sirci.

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Sirci, F., Goracci, L., Rodríguez, D. et al. Ligand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A1, A2A, A2B, and A3 receptor antagonists. J Comput Aided Mol Des 26, 1247–1266 (2012). https://doi.org/10.1007/s10822-012-9612-8

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