Structure-based design of estrogen receptor-beta selective ligands.
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.
Manas
Eric S
ES
Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. manase@wyeth.com
Unwalla
Rayomand J
RJ
Xu
Zhang B
ZB
Malamas
Michael S
MS
Miller
Chris P
CP
Harris
Heather A
HA
Hsiao
Chulai
C
Akopian
Tatos
T
Hum
Wah-Tung
WT
Malakian
Karl
K
Wolfrom
Scott
S
Bapat
Ashok
A
Bhat
Ramesh A
RA
Stahl
Mark L
ML
Somers
William S
WS
Alvarez
Juan C
JC
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
D001572:Benzofurans; D001583:Benzoxazoles; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands