Conformational analysis of bivalent estrogen receptor ligands: from intramolecular to intermolecular binding.

Chembiochem : a European Journal of Chemical Biology
Min ShanRainer Haag

Abstract

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.

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Citations

Oct 1, 2013·Bioconjugate Chemistry·Hanieh KhaliliSteve Brocchini
Nov 29, 2012·Journal of the American Chemical Society·Kalyan K SadhuNicolas Winssinger
Aug 17, 2012·The Journal of Chemical Physics·Marcus WeberRainer Haag
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Jul 1, 2015·Beilstein Journal of Organic Chemistry·Susanne Liese, Roland R Netz
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Aug 5, 2020·Angewandte Chemie·Gunnar BachemOliver Seitz
Jun 18, 2014·Journal of Medicinal Chemistry·Paul M LevineKent Kirshenbaum
Mar 30, 2019·Journal of Medicinal Chemistry·Kalanidhi PalanichamyAdam B Braunschweig

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