Abstract
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 α (ERα) and estrogen receptor β (ERβ), that the functional outcome of ligand binding can be inferred from its ability to simultaneously bind both ERα and ERβ 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 β 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.