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Conformational Analysis of Bivalent Estrogen Receptor Ligands: From Intramolecular to Intermolecular Binding
Author(s) -
Shan Min,
Bujotzek Alexander,
Abendroth Frank,
Wellner Anja,
Gust Ronald,
Seitz Oliver,
Weber Marcus,
Haag Rainer
Publication year - 2011
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201100529
Subject(s) - bivalent (engine) , chemistry , intramolecular force , affinities , binding affinities , intermolecular force , stereochemistry , cooperative binding , binding site , estrogen receptor , crystallography , biophysics , receptor , molecule , metal , biochemistry , biology , organic chemistry , cancer , breast cancer , genetics
The estrogen receptor binding affinities of bivalent raloxifene ligands tethered by flexible spacers of different lengths have been evaluated in vitro. Two bivalent binding modes, intra‐ and intermolecular, were hypothesized to explain their different binding properties. The binding affinities of these bivalent ligands in an aqueous environment are influenced by their conformations, which can be determined by 2D NMR and UV spectral methods. Moreover, computer modeling and simulations were performed to explain the binding modes of these bivalent ligands and to estimate the conformational entropy difference between their unbound and bound states. It was found that bivalent ligands tethered by long spacers had weaker binding affinities because of the shielding of the binding moieties that results from their folded conformations; those tethered by short spacers had stronger affinities because they exposed their ligands to the receptor.