We present the structure-based optimization of a series of estrogen receptor-
![](/images/gifchars/beta2.gif)
(ER
![](/images/gifchars/beta2.gif)
) selectivelig
ands. X-ray cocrystal structures of these lig
ands complexed to both ER
and ER
![](/images/gifchars/beta2.gif)
are described. Wealso discuss how molecular modeling was used to take advantage of subtle differences between the twobinding cavities in order to optimize selectivity for ER
![](/images/gifchars/beta2.gif)
over ER
![](/images/gifchars/alpha.gif)
. Quantum chemical calculations are utilizedto gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservativeresidue substitutions in the lig
and binding pocket, the most selective compounds have greater than 100-fold selectivity for ER
![](/images/gifchars/beta2.gif)
relative to ER
![](/images/gifchars/alpha.gif)
when measured using a competitive radiolig
and binding assay.