title: Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method.
abstract: Here, we demonstrate that a single biochemical assay is able to predict the tissue-selective pharmacology of an array of selective estrogen receptor modulators (SERMs). We describe an approach to classify estrogen receptor (ER) modulators based on dynamics of the receptor-ligand complex as probed with hydrogen/deuterium exchange (HDX) mass spectrometry. Differential HDX mapping coupled with cluster and discriminate analysis effectively predicted tissue-selective function in most, but not all, cases tested. We demonstrate that analysis of dynamics of the receptor-ligand complex facilitates binning of ER modulators into distinct groups based on structural dynamics. Importantly, we were able to differentiate small structural changes within ER ligands of the same chemotype. In addition, HDX revealed differentially stabilized regions within the ligand-binding pocket that may contribute to the different pharmacology phenotypes of the compounds independent of helix 12 positioning. In summary, HDX provides a sensitive and rapid approach to classify modulators of the estrogen receptor that correlates with their pharmacological profile.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Susie Y
authors.initials: SY
authors.lastname: Dai
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chalmers
authors.forename: John
authors.initials: J
authors.lastname: Bruning
authors.forename: Kelli S
authors.initials: KS
authors.lastname: Bramlett
authors.forename: Harold E
authors.initials: HE
authors.lastname: Osborne
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barr
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Minmin
authors.initials: M
authors.lastname: Wang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Dodge
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D001671:Biochemistry / Q000379:methods*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D003627:Data Interpretation, Statistical; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D011485:Protein Binding; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D020845:Selective Estrogen Receptor Modulators