Conformational analysis of thioglycoside derivatives of histo-blood group ABH antigens using an ab initio-derived reparameterization of MM4: implications for design of non-hydrolysable mimetics

  • Francesco Strino
  • Jenn-Huei Lii
  • Hans-Joachim Gabius
  • Per-Georg Nyholm


Histo-blood group ABH antigens serve as recognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor progression. Thus, they are of interest as a starting point for drug design. In this respect, potent non-hydrolysable derivatives such as thioglycosides are of special interest. As prerequisite to enable estimations of ligand properties relative to their natural counterparts, conformational properties of the thioglycosidic derivatives of ABH trisaccharides and their disaccharide units were calculated using systematic and filtered systematic searches with the MM4 force field. Parameters for the glycosidic torsions of thioglycosides were independently derived from ab initio calculations. The resulting energy deviations required a reparameterization of MM4 to a new parameter set called MM4R. The data sets obtained using MM4R reveal that the thioglycosides have somewhat increased levels of flexibility about the major low-energy conformations shared with the corresponding O-glycosides. In the trisaccharides, the thiosubstitution of the Gal[NAc]α1-3Gal linkage leads to a preference for a conformation which is the secondary minimum of the natural counterparts. This conformation also generates contacts between the N-acetyl group and the fucose moiety in the blood group A derivative. Calculations further indicate that thiosubstitution of only the Fucα1-2Gal linkage does not affect the conformational preferences compared to the natural trisaccharide. Thiosubstitution of both linkages in the trisaccharide results in increased flexibility but the favored conformation of the natural trisaccharides is preferred. The study suggests that thioglycoside derivatives of ABH antigens could have pharmaceutical interest as ligands of lectins and other carbohydrate-binding proteins.


Blood group antigens Drug design Lectins Molecular mechanics Thioglycoside 



Financial support from the Swedish Medical Research Council (K2000-03x-00006-36A), the research initiative LMUexcellent, an EC Marie Curie Research Training Network grant (MRTN-CT-2005-019561) and Biognos AB (Göteborg) is gratefully acknowledged. Also, access to the Linux cluster at the Institute of Biomedicine, Gothenburg University, Sweden is gratefully acknowledged.


  1. 1.
    Landsteiner K (1900) Zbl Bakt 27:357Google Scholar
  2. 2.
    Kilpatrick DC, Green C (1992) Adv Lectin Res 5:51Google Scholar
  3. 3.
    Watkins WM (1999) Trends Glycosci Glycotechnol 11:391Google Scholar
  4. 4.
    Reuter G, Gabius H-J (1999) Cell Mol Life Sci 55:368CrossRefGoogle Scholar
  5. 5.
    Gabius H-J, Siebert H-C, André S, Jiménez-Barbero J, Rüdiger H (2004) Chembiochem 5:740CrossRefGoogle Scholar
  6. 6.
    Le Pendu J (2004) Adv Exp Med Biol 554:135Google Scholar
  7. 7.
    Gabius H-J (2006) Crit Rev Immunol 26:43Google Scholar
  8. 8.
    Kayser K, Bovin NV, Korchagina EY, Zeilinger C, Zeng FY, Gabius H-J (1994) Eur J Cancer 30A:653CrossRefGoogle Scholar
  9. 9.
    Gabius H-J (2008) Biochem Soc Trans 36:1491CrossRefGoogle Scholar
  10. 10.
    Witczak ZJ (1999) Curr Med Chem 6:165Google Scholar
  11. 11.
    Jahn M, Marles J, Warren RAJ, Withers SG (2003) Angew Chem Int Ed Engl 42:352CrossRefGoogle Scholar
  12. 12.
    Rye CS, Withers SG (2004) Carbohydr Res 339:699CrossRefGoogle Scholar
  13. 13.
    Szilágyi L, Varela O (2006) Curr Org Chem 10:1745CrossRefGoogle Scholar
  14. 14.
    Kim Y-W, Lovering AL, Chen H, Kantner T, McIntosh LP, Strynadka NCJ, Withers SG (2006) J Am Chem Soc 128:2202CrossRefGoogle Scholar
  15. 15.
    André S, Pei Z, Siebert H-C, Ramström O, Gabius H-J (2006) Bioorg Med Chem 14:6314CrossRefGoogle Scholar
  16. 16.
    Wu AM, Wu JH, Liu J-H, Singh T, André S, Kaltner H, Gabius H-J (2004) Biochimie 86:317CrossRefGoogle Scholar
  17. 17.
    Wu AM, Singh T, Wu JH, Lensch M, André S, Gabius H-J (2006) Glycobiology 16:524CrossRefGoogle Scholar
  18. 18.
    Imberty A, Varrot A (2008) Curr Opin Struct Biol 18:567CrossRefGoogle Scholar
  19. 19.
    Tvaroska I (1984) Collect Czech Chem Commun 49:345Google Scholar
  20. 20.
    Aguilera B, Jiménez-Barbero J, Fernández-Mayoralas A (1998) Carbohydr Res 308:19CrossRefGoogle Scholar
  21. 21.
    Mazeau K, Tvaroska I (1992) Carbohydr Res 225:27CrossRefGoogle Scholar
  22. 22.
    Allinger NL, Yuh YH, Lii J-H (1989) J Am Chem Soc 111:8551CrossRefGoogle Scholar
  23. 23.
    Allinger NL, Rahman M, Lii J-H (1990) J Am Chem Soc 112:8293CrossRefGoogle Scholar
  24. 24.
    Lii J-H, Allinger NL (1991) J Comput Chem 12:186CrossRefGoogle Scholar
  25. 25.
    Allinger NL, Zhou X, Bergsma J (1994) J Mol Struct 312:69Google Scholar
  26. 26.
    Allinger NL, Chen K-H, Lii J-H, Durkin KA (2003) J Comput Chem 24:1447CrossRefGoogle Scholar
  27. 27.
    Lii J-H, Chen K-H, Durkin KA, Allinger NL (2003) J Comput Chem 24:1473CrossRefGoogle Scholar
  28. 28.
    Lii J-H, Chen K-H, Grindley TB, Allinger NL (2003) J Comput Chem 24:1490CrossRefGoogle Scholar
  29. 29.
    Lii J-H, Chen K-H, Allinger NL (2003) J Comput Chem 24:1504CrossRefGoogle Scholar
  30. 30.
    Lii J-H, Ma B, Allinger NL (1999) J Comput Chem 20:1593CrossRefGoogle Scholar
  31. 31.
    Nahmany A, Strino F, Rosen J, Kemp GJL, Nyholm P-G (2005) Carbohydr Res 340:1059CrossRefGoogle Scholar
  32. 32.
    Strino F, Nahmany A, Rosen J, Kemp GJL, Sá-correia I, Nyholm P-G (2005) Carbohydr Res 340:1019CrossRefGoogle Scholar
  33. 33.
    Heiden W, Moeckel G, Brickmann J (1993) J Comput Aided Mol Des 7:503CrossRefGoogle Scholar
  34. 34.
    Ghose AK, Viswanadhan VN, Wendoloski JJ (1998) J Phys Chem A 102:3762CrossRefGoogle Scholar
  35. 35.
    Matsuura H, Murata H (1983) J Mol Struct 96:267CrossRefGoogle Scholar
  36. 36.
    Azurmendi HF, Bush CA (2002) Carbohydr Res 337:905CrossRefGoogle Scholar
  37. 37.
    Gabius H-J (ed) (2009) The sugar code: fundamentals of glycosciences. Wiley–VCH, WenheimGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Francesco Strino
    • 1
  • Jenn-Huei Lii
    • 2
  • Hans-Joachim Gabius
    • 3
  • Per-Georg Nyholm
    • 1
  1. 1.Institute of Biomedicine/Section of Medical BiochemistryGöteborg UniversityGöteborgSweden
  2. 2.Department of ChemistryNational Changhua University of EducationChanghuaTaiwan
  3. 3.Institut für Physiologische Chemie, Tierärztliche FakultätLudwig-Maximilians-Universität MünchenMünchenGermany

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