Details

Autor(en) / Beteiligte

• Shan, Min
• Bujotzek, Alexander
• Abendroth, Frank
• Wellner, Anja
• Gust, Ronald
• Seitz, Oliver
• Weber, Marcus
• Haag, Rainer

Titel

Conformational Analysis of Bivalent Estrogen Receptor Ligands: From Intramolecular to Intermolecular Binding

Ist Teil von

• Chembiochem : a European journal of chemical biology, 2011-11, Vol.12 (17), p.2587-2598

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2011

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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. Shape up: Evaluation of estrogen receptor binding with 13 bivalent raloxifene ligands tethered by flexible spacers of different lengths in vitro and in silico indicated that ligand conformation significantly influenced the binding affinities in the aqueous environment. Moreover, two bivalent binding modes—intra‐ and intermolecular—were hypothesized to explain their different binding behaviors.