HQSAR and molecular docking studies of furanyl derivatives as adenosine A2A receptor antagonists

Abstract

Structure- and ligand-based computational design strategies were used to understand the molecular requirements of furanyl derivatives 2-(furan-2-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amines (TfPAs), 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (TaPAs), and 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amines (TTAs) as adenosine A2A receptor (A2AR) antagonists. First, we studied the structure–activity relationship of the selected compounds using hologram quantitative structure–activity relationship (HQSAR) methodology. The best model (training set included 67 compounds) included fragment parameters such as atoms (A), bonds (B), connections (C), and donors/acceptors groups (DA) and had a good q 2 value of 0.776 including size fragments of 7–10 and the hologram length of 199. It also predicted adequately the compounds contained in the test set (10 compounds). In addition, we studied the binding orientations of the higher and less active compounds using flexible molecular docking. We found orientations that are in agreement with previous reports.

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References

  1. Alves CN, Barroso LP, Santos LS, Jardim IN (1998) Quantitative structure activity relationship of compounds which are anti-schistosomiasis active. J Braz Chem Soc 9:577–582

    CAS  Article  Google Scholar 

  2. Alves CN, de Macedo LGM, Honorio KM, Camargo AJ, Santos LS, Jardim IN, Barata LES, da Silva ABF (2002) A structure–activity relationship (SAR) study of neolignan compounds with anti-schistosomiasis activity. J Braz Chem Soc 13:300–307

    CAS  Article  Google Scholar 

  3. Armentero MT, Pinna A, Ferré S, Lanciego JL, Müller CE, Franco R (2011) Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 132:280–299

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Bacilieri M, Ciancetta A, Paoletta S, Federico S, Cosconati S, Cacciari B, Taliani S, Settimo FDa, Novellino E, Klotz KN, Spalluto G, Moro S (2013) Revisiting a receptor-based pharmacophore hypothesis for human A(2A) adenosine receptor antagonists. J Chem Inf Model 53:1620–1637

    CAS  Article  PubMed  Google Scholar 

  5. Banks JL, Beard HS, Cao Y, Cho AE, Damm W, Farid R (2005) Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem 26:1752–1780

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Barnett-Cowan M, Dyde RT, Foxe SH, Moro E, Hutchison WD, Harris LR (2010) Multisensory determinants of orientation perception in Parkinson’s disease. Neuroscience 167:1138–1150

    CAS  Article  PubMed  Google Scholar 

  7. Bermejo PE (2007) Relación entre temblor esencial, enfermedad de Parkinson y demencia con cuerpos de Lewy. Rev Neurol 45:689–694

    CAS  PubMed  Google Scholar 

  8. Brassat D, Durr A, Agid Y, Brice A (1999) Genetic aspect of Parkinson’s disease. La Revue de Médecine Interne 20:709–714

    CAS  Article  PubMed  Google Scholar 

  9. Bussell R, Eliezer D (2004) Effects of Parkinson’s disease-linked mutations on the structure of lipid-associated alpha-synuclein. Biochemistry 43:4810–4818

    CAS  Article  PubMed  Google Scholar 

  10. Calgarotto AK, Miotto S, Honorio KM, da Silva ABF, Marangoni S, Silva JL, Comar M, Oliveira KMT, da Silva SL (2007) A multivariate study on flavonoid compounds scavenging the peroxynitrite free radical. J Mol Struct 808:25–33

    CAS  Article  Google Scholar 

  11. Camargo AJ, Mercadante R, Honorio KM, Alves CN, da Silva ABF (2002) A structure–activity relationship (SAR) study of synthetic neolignans and related compounds with biological activity against Escherichia coli. J Mol Struct 583:105–116

    CAS  Article  Google Scholar 

  12. Camargo AJ, Honorio KM, Mercadante R, Molfetta FA, Alves CN, da Silva ABF (2003) A study of neolignan compounds with biological activity against Paracoccidioides brasiliensis by using quantum chemical and chemometric methods. J Braz Chem Soc 14:809–814

    CAS  Article  Google Scholar 

  13. Castilho MS, Postigo MP, de Paula CBV, Montanari CA, Oliva G, Andricopulo AD (2006) Two- and three-dimensional quantitative structure–activity relationships for a series of purine nucleoside phosphorylase inhibitors. Bioorg Med Chem 14:516–527

    CAS  Article  PubMed  Google Scholar 

  14. Cramer RD III, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967

    CAS  Article  PubMed  Google Scholar 

  15. Davie CA (2008) A review of Parkinson’s disease. Br Med Bull 86:109–127

    CAS  Article  PubMed  Google Scholar 

  16. Devijver PA, Kittler J (1982) Pattern recognition—a statistical approach. Prentice-Hall, Engelwood Cliffs

    Google Scholar 

  17. Doré 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 of the adenosine A2A receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19:1283–1293

    Article  PubMed  PubMed Central  Google Scholar 

  18. Flower DR (1998) On the properties of bit string-based measures of chemical similarities. J Chem Inf Comput Sci 38:379–386

    CAS  Article  Google Scholar 

  19. Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph Mod 20:269–276

    CAS  Article  Google Scholar 

  20. Heritage TW, Lowis DR (1999). Molecular hologram QSAR. In: Rational drug design: novel methodology and practical applications. Oxford University Press, New York

  21. Hickey P, Stacy M (2012) Curr. Adenosine A2A antagonists in Parkinson’s disease: What’s next? Neurol Neurosci Rep 12:376–385

    CAS  Article  Google Scholar 

  22. Honorio KM, Garratt RC, Andricopulo AD (2005) Hologram quantitative structure–activity relationships for a series of farnesoid X receptor activators. Bioorg Med Chem Lett 15:3119–3125

    CAS  Article  PubMed  Google Scholar 

  23. Honorio KM, Garratt RC, Polikarpov I, Andricopulo AD (2006) Hologram QSAR studies on farnesoid X receptor activators. Lett Drug Des Discov 3:261–267

    CAS  Article  Google Scholar 

  24. Honorio KM, Salum LB, Garratt RC, Polikarpov I, Andricopulo AD (2008) Two- and three-dimensional quantitative structure–activity relationships studies on a series of liver X receptor ligands. Open Med Chem J 2:87–96

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Jankovic JJ (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376

    CAS  Article  PubMed  Google Scholar 

  26. Keddie JR, Poucher SM, Shaw GR, Brooks R, Collis MG (1996) In vivo characterisation of ZM 241385, a selective adenosine A2A receptor antagonist. Eur J Pharmacol 301:107–113

    CAS  Article  PubMed  Google Scholar 

  27. Kim SK, Gao ZG, Van Rompaey P, Gross AS, Chen A, Van Calenbergh S (2003) Modeling the adenosine receptors: comparison of the binding domains of A2A agonists and antagonists. J Med Chem 46:4847–4859

    CAS  Article  PubMed  Google Scholar 

  28. Kirchmair J, Wolber G, Laggner C, Langer T (2006) Comparative performance assessment of the conformational model generators omega and catalyst: a large-scale survey on the retrieval of protein-bound ligand conformations. J Chem Inf Model 46:1848–1861

    CAS  Article  PubMed  Google Scholar 

  29. Knuth DE (1973) Sorting and searching. Addison-Wesley, Massachusetts

    Google Scholar 

  30. Kulisevsky J, Poyurovsky M (2012) Adenosine A2A-receptor antagonism and pathophysiology of Parkinson’s disease and drug-induced movement disorders. Eur Neurol 67:4–11

    CAS  Article  PubMed  Google Scholar 

  31. Lowis DR (1997) HQSAR: a new, highly predictive QSAR technique. Tripos Tech Notes 1(5):17

    Google Scholar 

  32. Matasi J, Caldwell JP, Zhang H, Fawzi A, Cohen-Williams ME, Varty GB, Deen B (2005) 2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs: highly potent, orally active, adenosine A2A antagonists. Part 1. Bioorg Med Chem Lett 15:3670–3674

    CAS  Article  PubMed  Google Scholar 

  33. Michielan L, Bacilieri M, Schiesaro A, Bolcato C, Pastorin G, Spalluto G, Cacciari B, Klotz KN, Kaseda C, Moro S (2008) Linear and nonlinear 3D-QSAR approaches in tandem with ligand-based homology modeling as a computational strategy to depict the pyrazolo-triazolo-pyrimidine antagonists binding site of the human adenosine A2A receptor. J Chem Inf Model 48:350–363

    CAS  Article  PubMed  Google Scholar 

  34. Moda TL, Montanari CA, Andricopulo AD (2007) Hologram QSAR model for the prediction of human oral bioavailability. Bioorg Med Chem 15:7738–7745

    CAS  Article  PubMed  Google Scholar 

  35. Morales-Bayuelo A, Vivas-Reyes R, Ayazo H (2010) Three-dimensional quantitative structure–activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists. Eur J Med Chem 45:4509–4522

    CAS  Article  PubMed  Google Scholar 

  36. Mota SGR, Barros TF, Castilho MS (2009) 2D QSAR studies on a series of bifonazole derivatives with antifungal activity. J Braz Chem Soc 20:451–459

    CAS  Article  Google Scholar 

  37. Noyes K, Dick AW, Holloway RG (2006) Pramipexole versus levodopa in patients with early Parkinson’s disease: effect on generic and disease-specific quality of life. Value Health (ISPOR) 9:28–38

    Article  Google Scholar 

  38. Olsson MHM, Søndergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 7:525–537

    CAS  Article  PubMed  Google Scholar 

  39. Pankratz N, Marder KS, Halter CA, Rudolph A, Shults CW, Nichols WC, Foroud T (2008) Clinical correlates of depressive symptoms in familial Parkinson’s disease. Movement disorders: off. Mov Disord Off J Mov Disord Soc 23:2216–2223

    Article  Google Scholar 

  40. Pinheiro AAC, Borges RS, Santos LS, Alves CN (2004) A QSAR study of 8.O.4-neolignans with antifungal activity. J Mol Struct 672:215–219

    CAS  Article  Google Scholar 

  41. Poucher SM, Keddie JR, Singh P, Stoggall SM, Caulkett PW, Jones G, Coll MG (1995) The in vitro pharmacology of ZM 241385, a potent, non-xanthine, A2a selective adenosine receptor antagonist. Br J Pharmacol 115:1096–1102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Poucher SM, Keddie JR, Brooks R, Shaw GR, McKillop D (1996) Pharmacodynamics of ZM 241385, a potent A2a adenosine receptor antagonist, after enteric administration in rat, cat and dog. J Pharm Pharmacol 48:601–606

    CAS  Article  PubMed  Google Scholar 

  43. Qin Z, Zhang L, Sun F, Fang F, Meng C, Tanner C, Chan P (2009) Health related quality of life in early Parkinson’s disease: impact of motor and non-motor symptoms, results from Chinese levodopa exposed cohort. Parkinsonism Relat Disord 15:767–771

    Article  PubMed  Google Scholar 

  44. Ron K (1995) A study of cross-validation and bootstrap for accuracy estimation and model selection. Proc Four Int Jt Conf Artif Intell (San Mateo, CA: Morgan Kaufmann) 2(12):1137–1143

    Google Scholar 

  45. Salum LB, Polikarpov I, Andricopulo AD (2007) Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies. J Mol Graph Model 25:434–442

    Article  Google Scholar 

  46. Salum LB, Dias LC, Andricopulo AD (2009) Structural and chemical basis for anticancer activity of a series of β-tubulin ligands: molecular modeling and 3D QSAR studies. J Braz Chem Soc 20:693–703

    CAS  Article  Google Scholar 

  47. Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363:1783–1793

    CAS  Article  PubMed  Google Scholar 

  48. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234

    Article  PubMed  Google Scholar 

  49. Schrödinger Suite 2014-2 Induced Fit Docking protocol; Glide version 6.3, Schrödinger, LLC, New York, NY, 2014; Prime version 3.6, Schrödinger, LLC, New York, NY, 2014 (n.d.)

  50. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 49:534–553

    CAS  Article  PubMed  Google Scholar 

  51. Tong W, Lowis DR, Perkins R, Chen Y, Welsh WJ, Goddette DW, Heritage TW, Sheehan DM (1998) Evaluation of quantitative structure–activity relationship methods for large-scale prediction of chemicals binding to the estrogen receptor. J Chem Inf Comput Sci 38:669–677

    CAS  Article  PubMed  Google Scholar 

  52. Valadares NF, Castilho MS, Polikarpov I, Garratt RC (2007) 2D QSAR studies on thyroid hormone receptor ligands. Bioorg Med Chem 15:4609–4617

    CAS  Article  PubMed  Google Scholar 

  53. Vargas LM (2007) Enfermedad de Parkinson y la Dopamina. BUN Synapsis 2:12–16

    Google Scholar 

  54. Venhuis BJ, Wikström HV, Rodenhuis N, Sundell S, Dijkstra D (2002) A new type of prodrug of catecholamines: an opportunity to improve the treatment of Parkinson’s disease. J Med Chem 45:2349–2351

    CAS  Article  PubMed  Google Scholar 

  55. Vu CB, Shields P, Peng B (2004) Triamino derivatives of triazolotriazine and triazolopyrimidine as adenosine A2a receptor antagonists. Bioorg Med Chem Lett 14:4835–4838

    CAS  Article  PubMed  Google Scholar 

  56. Weber KC, Honorio KM, Andricopulo AD, da Silva ABF (2008) Two-dimensional QSAR studies on arylpiperazines as high-affinity 5-HT1A receptor ligands. Med Chem 4:328–335

    CAS  Article  PubMed  Google Scholar 

  57. Wold S (1978) Cross-validatory estimation of the number of components in factor and principal component models. Technometrics 4:397–405

    Article  Google Scholar 

  58. Xiang YH, Zhang ZY, Xiao AJ, Huo JX (2009) Recent studies of QSAR on inhibitors of estrogen receptor and human eosinophil phosphodiesterase. Curr Comput Aided Drug Des 5:200–214

    CAS  Article  Google Scholar 

  59. Yan H, Pan XL, Tan NH, Fan JT, Zeng GZ, Han HJ (2009) 2D- and 3D-QSAR studies on 54 anti-tumor Rubiaceae-type cyclopeptides. Eur J Med Chem 44:3425–3432

    CAS  Article  PubMed  Google Scholar 

  60. Yao G, Haque S, Sha L, Kumaravel G, Wang J, Engber TM, Whalley E, Conlon PR, Chang H, Kiesman WF, Petter RC (2005) Synthesis of alkyne derivatives of a novel triazolopyrazine as A(2A) adenosine receptor antagonists. Bioorg Med Chem Lett 15:511–515

    CAS  Article  PubMed  Google Scholar 

  61. Young D (2001). Computational chemistry: a practical guide for applying techniques to real-world problems. Comput Chem. Appendix A. A.3.2 pg 342

  62. Zanatta N, Borchhardt DM, Carpes AD, Marchia TM, Andricopulo AD, Salum LB, Schetinger MRC, Bonacorso HG, Martins MAR, Flores AEC (2008) Synthesis, screening for antiacetylcholinesterase activity and binding mode prediction of a new series of [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters. J Braz Chem Soc 19:1118–1124

    CAS  Article  Google Scholar 

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Acknowledgments

A. M. B. thanks to the Universidad de Talca (CBSM) for the continuous support to this investigation, to the postdoctoral Project No. 3150035 (FONDECYT, CHILE). C. M. G. acknowledges support from doctoral fellowship CONICYT-PCHA/Folio 21120214. J. C. acknowledges funds of the Project FONDECYT 1130141.

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Correspondence to Alejandro Morales-Bayuelo.

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Muñoz-Gutiérrez, C., Caballero, J. & Morales-Bayuelo, A. HQSAR and molecular docking studies of furanyl derivatives as adenosine A2A receptor antagonists. Med Chem Res 25, 1316–1328 (2016). https://doi.org/10.1007/s00044-016-1575-1

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Keywords

  • Parkinson’s disease
  • Adenosine (A2A) receptor
  • HQSAR
  • Molecular docking