Skip to main content
Log in

Docking of sialic acid analogues against influenza A hemagglutinin: a correlational study between experimentally measured and computationally estimated affinities

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript


A molecular docking tool of AutoDock3.05 was evaluated for its ability to reproduce experimentally determined affinities of various sialic acid analogues toward hemagglutinin of influenza A virus. With the exception of those with a C6-modified glycerol side chain, the experimental binding affinities of most sialic acid analogues (C2, C4 and C5-substituted) determined by viral hemadsorption inhibition assay, hemagglutination inhibition assay and nuclear magnetic resonance correlated well with the computationally estimated free energy of binding. Sialic acid analogues with modified glycerol side chains showed only poor correlation between the experimentally determined hemagglutinin inhibitor affinities and AutoDock3.05 scores, suggesting high mobility of the glutamic acid side chain at the glycerol binding pocket, which is difficult to simulate using a flexi-rigid molecular docking approach. In conclusion, except for some glycerol-substituted sialic acid analogues, the results showed the effectiveness of AutoDock3.05 searching and scoring functions in estimating affinities of sialic acid analogues toward influenza A hemagglutinin, making it a reliable tool for screening a database of virtually designed sialic acid analogues for hemagglutinin inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Scheme 1
Scheme 2
Scheme 3
Fig. 2
Fig. 3a–c
Fig. 4a,b
Fig. 5

Similar content being viewed by others


  1. Fouchier RAM, Munster V, Wallensten A, Bestebroer TM, Herfst S, Smith D, Rimmelzwaan GF, Olsen B, Osterhaus ADME (2005) Characterization of a novel influenza a virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 79:2814–2882

    Article  CAS  Google Scholar 

  2. Baker AT, Varghese JN, Laver WG, Colman PM (1987) Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus. Proteins 2:111–117

    Article  CAS  Google Scholar 

  3. Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569

    Article  CAS  Google Scholar 

  4. Air GM, Laver WG (1989) The neuraminidase of influenza virus. Proteins Struc Funct Genet 6:341–356

    Article  CAS  Google Scholar 

  5. Wagner R, Matrosovich M, Klenk HD (2002) Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol 12:159–166

    Article  Google Scholar 

  6. Varki NM, Varki A (2007) Diversity in cell surface sialic acid presentations: implications for biology and disease. Lab Invest 87:851–857

    Article  CAS  Google Scholar 

  7. Matrosovich M, Klenk H-D (2003) Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Rev Med Virol 13:85–97

    Article  CAS  Google Scholar 

  8. Carlescu I, Scutaru D, Popa M, Uglea CV (2009) Synthetic sialic-acid-containing polyvalent antiviral inhibitors. Med Chem Res 18:477–494

    Article  CAS  Google Scholar 

  9. Hurt AC, Ernest J, Deng Y-M, Iannello P, Besselaar TG, Birch C, Buchy P, Chittaganpitch M, Chiu S-C, Dwyer D, Guigon A, Harrower B, Kei IP, Kok T, Lin C, McPhie K, Mohd A, Olveda R, Panayotou T, Rawlinson W et al (2009) Emergence and spread of oseltamivir-resistant A(H1N1) influenza viruses in Oceania, South East Asia and South Africa. Antivir Res 83:90–93

    Article  CAS  Google Scholar 

  10. Weis W, Brown JH, Cusack S, Paulson JC, Skehel JJ, Wiley DC (1988) Structure of the influenza virus hemagglutinin complexed with its receptor sialic acid. Nature 333:426–431

    Article  CAS  Google Scholar 

  11. Sauter NK, Hanson JE, Glick GD, Brown JH, Crowther RL, Park SJ, Skehel JJ, Wiley DC (1992) Binding of influenza virus hemagglutinin to analogs of its cell-surface receptor, sialic acid: analysis by proton nuclear magnetic resonance spectroscopy and X-ray crystallography. Biochemistry 31:9609–9621

    Article  CAS  Google Scholar 

  12. Sauter NK, Bednarski MD, Wurzburg BA, Hanson JE, Whitesides GM, Skehel JJ, Wiley DC (1989) Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants: a 500 MHz proton nuclear magnetic resonance study. Biochemistry 28:8388–8396

    Article  CAS  Google Scholar 

  13. Machytka D, Kharitonenkov I, Isecke R, Hetterich P, Brossmer R, Klein RA, Klenk HD, Egge H (1993) Methyl alpha-glycoside of N-thioacetyl-D-neuraminic acid: a potential inhibitor of influenza A virus. A 1H NMR study. FEBS Lett 334:117–120

    Article  CAS  Google Scholar 

  14. Hanson JE, Sauter NK, Skehel JJ, Wiley DC (1992) Proton nuclear magnetic resonance studies of the binding of sialosides to intact influenza virus. Virology 189:525–533

    Article  CAS  Google Scholar 

  15. Pritchett TJ (1987) Receptor analogue inhibitors of influenza virus adsorption and infection. PhD thesis, University of California, Los Angeles

  16. Klem S, Paulson JC, Rose U, Brossmer R, Schmid W, Bandgar BP, Schreiner E, Hartmann M, Zbiral E (1992) Use of sialic acid analogues to define functional groups involved in binding to the influenza virus hemagglutinin. Eur J Biochem 205:147–153

    Article  Google Scholar 

  17. Toogood PL, Galliker PK, Glick GD, Knowles JR (1991) Monovalent sialosides that bind tightly to influenza A virus. J Med Chem 34:3138–3140

    Article  CAS  Google Scholar 

  18. Al-Qattan MN, Mordi MN (2009) Site-directed fragment-based generation of virtual sialic acid databases against influenza A hemagglutinin. J Mol Model (in press) online first: doi:10.1007/s00894-009-0606-y

  19. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  20. Olsen L, Pettersson I, Hemmingsen L, Adolph H-W, Jorgenson FS (2004) Docking and scoring of metallo-β-lactamases inhibitors. J Comput Aided Mol Des 18:287–302

    Article  CAS  Google Scholar 

  21. Bellocchi D, Macchiarulo A, Costantino G, Pellicciari R (2005) Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule. Bioorg Med Chem 13:1151–1157

    Article  CAS  Google Scholar 

  22. Hu X, Stebbins CE (2005) Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphate YopH inhibitors. Bioorg Med Chem 13:1101–1109

    Article  CAS  Google Scholar 

  23. Zheng M, Yu K, Liu H, Luo X, Chen K, Zhu W, Jiang H (2006) QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR. J Comput Aided Mol Des 20:549–566

    Article  CAS  Google Scholar 

  24. Davis AM, Teague SJ, Kleywegt GJ (2003) Application and limitations of X-ray crystallographic data in structure-based ligand and drug design. Angew Chem Int Ed 42:2718–2736

    Article  CAS  Google Scholar 

  25. Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152

    Article  CAS  Google Scholar 

  26. Pearlman DA, Charifson PS (2001) Are free energy calculations useful in practice? A comparison with rapid scoring functions for the p38 MAP kinase protein system. J Med Chem 44:3417–1152

    Article  CAS  Google Scholar 

  27. Ewing TJA, Makino S, Skillman AG, Kuntz ID (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des 15:411–428

    Article  CAS  Google Scholar 

  28. Hanessian S, Moitessier N, Therrien E (2001) A comparative docking study and the design of potentially selective MMP inhibitors. J Comput Aided Mol Des 15:873–881

    Article  CAS  Google Scholar 

Download references


Mr. Al-qattan appreciates Universiti Sains Malaysia for supporting this project through a research fellowship scheme.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Mohd Nizam Mordi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Al-qattan, M.N., Mordi, M.N. Docking of sialic acid analogues against influenza A hemagglutinin: a correlational study between experimentally measured and computationally estimated affinities. J Mol Model 16, 1047–1058 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: