Skip to main content
SpringerLink
Log in

Towards a rational spacer design for bivalent inhibition of estrogen receptor

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Estrogen receptors are known drug targets that have been linked to several kinds of cancer. The structure of the estrogen receptor ligand binding domain is available and reveals a homodimeric layout. In order to improve the binding affinity of known estrogen receptor inhibitors, bivalent compounds have been developed that consist of two individual ligands linked by flexible tethers serving as spacers. So far, binding affinities of the bivalent compounds do not surpass their monovalent counterparts. In this article, we focus our attention on the molecular spacers that are used to connect the individual ligands to form bivalent compounds, and describe their thermodynamic contribution during the ligand binding process. We use computational methods to predict structural and entropic parameters of different spacer structures. We find that flexible spacers introduce a number of effects that may interfere with ligand binding and possibly can be connected to the low binding affinities that have been reported in binding assays. Based on these findings, we try to provide guidelines for the design of novel molecular spacers.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Avendano C, Menendez JC (2008) Medicinal chemistry of anticancer drugs. Elsevier B.V., Amsterdam

    Google Scholar 

  2. Berendsen HJC, Postma JPM, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  3. Bergmann KE, Woogef CH, Carlson KE, Katzenellenbogen BS, Katzenellenbogen JA (1994) Bivalent ligands as probes of estrogen receptor action. J Steroid Biochem Mol Biol 49:139–152

    Article  CAS  Google Scholar 

  4. Berube G, Rabouin D, Perron V, N’Zemba B, Gaudreault RC, Parent S, Asselin E (2006) Synthesis of unique 17β-estradiol homo-dimers, estrogen receptors binding affinity evaluation and cytocidal activity on breast, intestinal and skin cancer cell lines. Steroids 71:911–921

    Article  CAS  Google Scholar 

  5. Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engstroem O, Oehman L, Greene GL, Gustafsson J, Carlquis M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758

    CAS  Google Scholar 

  6. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:14–101

    Article  Google Scholar 

  7. Case D, III, TEC, Darden T, Gohlke H, Luo R, Jr., KMM, Onufriev A, Simmerling C, Wang B, Woods R (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688

  8. Dai SY, Chalmers MJ, Bruning J, Bramlett KS, Osborne HE, Montrose-Rafizadeh C, Barr RJ, Wang Y, Wang M, Burris TP, Dodge JA, Griffin PR (2008) Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method. Proc Natl Acad Sci 105(20):7171–7176

    Article  CAS  Google Scholar 

  9. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8592

    Article  CAS  Google Scholar 

  10. Groleau S, Nault J, Lepage M, Couturea M, Dallaire N, Berube G, C-Gaudreault R (1999) Synthesis and preliminary in vitro cytotoxic activity of new triphenylethylene dimers. Bioorg Chem 27(5):383–394

    Article  CAS  Google Scholar 

  11. Lee HJ, Lee HB, Andrade JD (1995) Blood compatibility of polyethylene oxide surfaces. Prog Polym Sci 20:1043–1079

    Article  CAS  Google Scholar 

  12. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  13. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447

    Article  CAS  Google Scholar 

  14. Horn HW, Swope WC, Pitera JW, Madura JD, Dick TJ, Hura GL, Head-Gordon T (2004) Development of an improved four-site water model for biomolecular simulations: TIP4P-Ew. J Chem Phys 120:9665–9678

    Article  CAS  Google Scholar 

  15. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C (2006) Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins 65:712–725

    Article  CAS  Google Scholar 

  16. Jakalian A, Bush BL, Jack DB, Bayly CI (2000) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. J Comput Chem 21:132–146

    Article  CAS  Google Scholar 

  17. Jakalian A, Jack DB, Bayly CI (2002) Fast, efficient generation of high-quality atomic charges AM1-BCC model: II Parameterization and validation. J Comput Chem 23:1623–1641

    Article  CAS  Google Scholar 

  18. Jordan VC (2003) Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1. Receptor interactions. J Med Chem 46:883–903

    Article  CAS  Google Scholar 

  19. Jordan VC (2003) Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J Med Chem 46:1081–1111

    Article  CAS  Google Scholar 

  20. Klimm M, Bujotzek A, Weber M (2010) Direct reweighting strategies in conformation dynamics. MATCH Commun Math Comput Chem 65(2) (in press)

  21. Kreuzer HJ, Wang RLC, Grunze M (1999) Effect of stretching on the molecular conformation of oligo (ethylene oxide): a theoretical study. New J Phys 1:21.1–21.16

    Article  Google Scholar 

  22. LaFrate AL, Carlson KE, Katzenellenbogen JA (2009) Steroidal bivalent ligands for the estrogen receptor: design, synthesis, characterization and binding affinities. Bioorg Med Chem 17:3528–3535

    Article  CAS  Google Scholar 

  23. Mammen M, Choi S, Whitesides GM (1998) Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed 37:2754–2794

    Article  Google Scholar 

  24. Ottow E, Weinmann H (2008) Nuclear receptors as drug targets. WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

    Book  Google Scholar 

  25. Rao J, Lahiri J, Weis RM, Whitesides GM (2000) Design, synthesis, and characterization of a high-affinity trivalent system derived from vancomycin and L-Lys-D-Ala-D-Ala. J Am Chem Soc 122:2698–2710

    Article  CAS  Google Scholar 

  26. Salomonsson M, Häggblad J, O’Malley BW, Sitbon GM (1994) The human estrogen receptor hormone binding domain dimerizes independently of ligand activation. J Steroid Biochem Mol Biol 48:447–452

    Article  CAS  Google Scholar 

  27. Schmidt-Ehrenberg J, Baum D, Hege HC (2002) Visualizing dynamic molecular conformations. In: Proceedings of IEEE visualization 2002. IEEE Computer Society Press, pp 235–242

  28. Sorin EJ, Pande VS (2005) Exploring the helix-coil transition via all-atom equilibrium ensemble simulations. Biophys J 88(4):2472–2493

    Article  CAS  Google Scholar 

  29. Stalling D, Westerhoff M, Hege HC (2005) Amira: a highly interactive system for visual data analysis. In: Hansen CD, Johnson CR (eds) The visualization handbook, chap. 38. Elsevier, UK, pp 749–767

    Chapter  Google Scholar 

  30. Wang J, Wang W, Kollman PA, Case DA (2006) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graphics Model 25:247–260

    Article  Google Scholar 

  31. Wang J, Wolf RM, Caldwell J, Kollman PA, Case DA (2004) Development and testing of a general Amber force field. J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  32. Weber M, Andrae K (2010) A simple method for the estimation of entropy differences. MATCH Commun Math Comput Chem 63(2):319–332

    CAS  Google Scholar 

  33. Wendlandt AE, Yelton SM, Lou D, Watt DS, Noonan DJ (2010) Synthesis and functional analysis of novel bivalent estrogens. Steroids 75:825–833

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Support by the Deutsche Forschungsgemeinschaft (SFB 765) is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Zuse Institute Berlin, Takustraße 7, 14195, Berlin, Germany

    Alexander Bujotzek & Marcus Weber

  2. Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 3, 14195, Berlin, Germany

    Min Shan & Rainer Haag

Authors
  1. Alexander Bujotzek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rainer Haag
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcus Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Bujotzek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bujotzek, A., Shan, M., Haag, R. et al. Towards a rational spacer design for bivalent inhibition of estrogen receptor. J Comput Aided Mol Des 25, 253–262 (2011). https://doi.org/10.1007/s10822-011-9417-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-011-9417-1

Keywords

Search

Navigation