title: Multiple-targeting and conformational selection in the estrogen receptor: computation and experiment.
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.
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Peng
authors: P
authors: Yuan
authors: Kaiwei
authors: K
authors: Liang
authors: Buyong
authors: B
authors: Ma
authors: Nan
authors: N
authors: Zheng
authors: Ruth
authors: R
authors: Nussinov
authors: Jian
authors: J
authors: Huang
mesh_terms: D016503:Drug Delivery Systems; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011960:Receptors, Estrogen / Q000187:drug effects*
chemical_list: D004965:Estrogen Antagonists; D008024:Ligands; D011960:Receptors, Estrogen