title: Structure-based design of estrogen receptor-beta selective ligands.
abstract: We present the structure-based optimization of a series of estrogen receptor-beta (ERbeta) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERalpha and ERbeta are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERbeta over ERalpha. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERbeta relative to ERalpha when measured using a competitive radioligand binding assay.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. manase@wyeth.com
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.forename: Rayomand J
authors.initials: RJ
authors.lastname: Unwalla
authors.forename: Zhang B
authors.initials: ZB
authors.lastname: Xu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Chris P
authors.initials: CP
authors.lastname: Miller
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harris
authors.forename: Chulai
authors.initials: C
authors.lastname: Hsiao
authors.forename: Tatos
authors.initials: T
authors.lastname: Akopian
authors.forename: Wah-Tung
authors.initials: WT
authors.lastname: Hum
authors.forename: Karl
authors.initials: K
authors.lastname: Malakian
authors.forename: Scott
authors.initials: S
authors.lastname: Wolfrom
authors.forename: Ashok
authors.initials: A
authors.lastname: Bapat
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Bhat
authors.forename: Mark L
authors.initials: ML
authors.lastname: Stahl
authors.forename: William S
authors.initials: WS
authors.lastname: Somers
authors.forename: Juan C
authors.initials: JC
authors.lastname: Alvarez
mesh_terms: D000595:Amino Acid Sequence; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism; D001583:Benzoxazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011789:Quantum Theory; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001572:Benzofurans; D001583:Benzoxazoles; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands