Journal of Computer-Aided Molecular Design

, Volume 25, Issue 3, pp 253–262

Towards a rational spacer design for bivalent inhibition of estrogen receptor

  • Alexander Bujotzek
  • Min Shan
  • Rainer Haag
  • Marcus Weber
Article

DOI: 10.1007/s10822-011-9417-1

Cite this article as:
Bujotzek, A., Shan, M., Haag, R. et al. J Comput Aided Mol Des (2011) 25: 253. doi:10.1007/s10822-011-9417-1

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.

Keywords

Estrogen receptorBivalent ligandSpacerMultivalencyEntropy

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Alexander Bujotzek
    • 1
  • Min Shan
    • 2
  • Rainer Haag
    • 2
  • Marcus Weber
    • 1
  1. 1.Zuse Institute BerlinBerlinGermany
  2. 2.Institute of Chemistry and BiochemistryFreie Universität BerlinBerlinGermany