Conformational analysis of bivalent estrogen receptor ligands: from intramolecular to intermolecular binding.
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.
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
Min
M
Shan
Alexander
A
Bujotzek
Frank
F
Abendroth
Anja
A
Wellner
Ronald
R
Gust
Oliver
O
Seitz
Marcus
M
Weber
Rainer
R
Haag
D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000378:metabolism
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D020849:Raloxifene Hydrochloride