**7. References**


As we look to the future of rational and structure-based drug design for the steroid receptors there remain key areas and questions that will dominate research in the short to medium term: 1. Is each of the five described methods for generating partial compounds equally applicable for each of the receptors? It is generally considered true that ERβ is easier to antagonize than ERα. This is most likely due to the agonist conformation of ERβ being less intrinsically stable than ERα and therefore ensuring that ERβ is more sensitive than

2. Does the choice of the mechanism for instilling partiality affect the eventual biological activity? Does a compound with a 40% reduction in agonistic activity due to a clash with helix-12 have the same biological effect as a compound with a 40% reduction in

3. As described earlier, partial agonists and antagonists are often poor candidates for cocrystallization Recently we have seen the first publications describing methods to circumvent this problem, either by introducing stabilizing mutations into the receptor (Bohl et al, 2007;Fagart et al, 2005;Nettles et al, 2008;Sack et al, 2001) or by generating stable crystals of the receptor using a receptor stabilizing ligand and then exchanging this compound with other compounds of interest via soaking (Raaijmakers, Versteegh, and Uitdehaag, 2009). Both approaches have the potential to dramatically increase our

understanding of the biological mechanisms underpinning partial agonism.

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**6. Conclusion** 

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