PMID- 15548008
OWN - NLM
STAT- MEDLINE
DCOM- 20050113
LR  - 20041119
IS  - 0002-7863 (Print)
IS  - 0002-7863 (Linking)
VI  - 126
IP  - 46
DP  - 2004 Nov 24
TI  - Structure-based design of estrogen receptor-beta selective ligands.
PG  - 15106-19
AB  - 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.
FAU - Manas, Eric S
AU  - Manas ES
AD  - Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, 
      Collegeville, Pennsylvania 19426, USA. manase@wyeth.com
FAU - Unwalla, Rayomand J
AU  - Unwalla RJ
FAU - Xu, Zhang B
AU  - Xu ZB
FAU - Malamas, Michael S
AU  - Malamas MS
FAU - Miller, Chris P
AU  - Miller CP
FAU - Harris, Heather A
AU  - Harris HA
FAU - Hsiao, Chulai
AU  - Hsiao C
FAU - Akopian, Tatos
AU  - Akopian T
FAU - Hum, Wah-Tung
AU  - Hum WT
FAU - Malakian, Karl
AU  - Malakian K
FAU - Wolfrom, Scott
AU  - Wolfrom S
FAU - Bapat, Ashok
AU  - Bapat A
FAU - Bhat, Ramesh A
AU  - Bhat RA
FAU - Stahl, Mark L
AU  - Stahl ML
FAU - Somers, William S
AU  - Somers WS
FAU - Alvarez, Juan C
AU  - Alvarez JC
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Am Chem Soc
JT  - Journal of the American Chemical Society
JID - 7503056
RN  - 0 (Benzofurans)
RN  - 0 (Benzoxazoles)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (Ligands)
SB  - IM
MH  - Amino Acid Sequence
MH  - Benzofurans/chemistry/metabolism
MH  - Benzoxazoles/chemistry/metabolism
MH  - Binding Sites
MH  - Binding, Competitive
MH  - Crystallography, X-Ray
MH  - Estrogen Receptor alpha/chemistry/metabolism
MH  - Estrogen Receptor beta/*chemistry/*metabolism
MH  - Humans
MH  - Ligands
MH  - Male
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Protein Conformation
MH  - Quantum Theory
MH  - Radioligand Assay
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
EDAT- 2004/11/19 09:00
MHDA- 2005/01/14 09:00
CRDT- 2004/11/19 09:00
PHST- 2004/11/19 09:00 [pubmed]
PHST- 2005/01/14 09:00 [medline]
PHST- 2004/11/19 09:00 [entrez]
AID - 10.1021/ja047633o [doi]
PST - ppublish
SO  - J Am Chem Soc. 2004 Nov 24;126(46):15106-19. doi: 10.1021/ja047633o.