Multiple-Targeting and Conformational Selection in the Estrogen Receptor: Computation and Experiment

Conformational selection is a primary mechanism in biomolecular recognition. The conformational ensemble may determine the ability of a drug to compete with a native ligand for a receptor target. Traditional docking procedures which use one or few protein structures are limited and may not be able to represent a complex competition among closely related protein receptors in agonist and antagonist ensembles. Here, we test a protocol aimed at selecting a drug candidate based on its ability to synergistically bind to distinct conformational states. We demonstrate, for the case of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta), that the functional outcome of ligand binding can be inferred from its ability to simultaneously bind both ER alpha and ER beta in agonist and antagonist conformations as calculated docking scores. Combining a conformational selection method with an experimental reporter gene system in yeast, we propose that several phytoestrogens can be novel estrogen receptor beta selective agonists. Our work proposes a computational protocol to select estrogen receptor subtype selective agonists. Compared with other models, present method gives the best prediction in ligands' function.

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