Conformational analysis of bivalent estrogen receptor ligands: from intramolecular to intermolecular binding |
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Authors: | Shan Min Bujotzek Alexander Abendroth Frank Wellner Anja Gust Ronald Seitz Oliver Weber Marcus Haag Rainer |
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Affiliation: | 1. Institut für Chemie und Biochemie, Freie Universit?t Berlin, Takustrasse 3, 14195 Berlin (Germany);2. Zuse Institut Berlin, Takustrasse 7, 14195 Berlin (Germany);3. Institut für Chemie, Humboldt‐Universit?t zu Berlin, Brook‐Taylor‐Strasse 2, 12489 Berlin (Germany);4. Institute of Pharmacy, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52a, A‐6020 Innsbruck (Austria) |
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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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Keywords: | conformation analysis drug design hormones multivalency structure–activity relationships |
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