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Introduction

(Some sections below taken from primary paper) Further introduction for estrogen receptors later and why useful

- "The gonadal steroid hormone estradiol, 1, exerts genomic actions through two oestrogen receptor subtypes, ERa and ERb. Emerging evidence has suggested that the function of ERb in contrast to ERa, potentially counteracts the proliferative effects of ERa on breast and endometrial tissue as well as being potentially responsible for the immunomodulatory as well as neuropharmacological behaviour of estradiol 1,2 There has been significant interest in the potential therapeutic benefit of selective ERb agonists to treat a variety of conditions including endometriosis3 and inflammatory bowel disease."

- A series of p-hydroxybenzenesulphonamides ERb receptor agonists were discovered and several compounds identified had excellent selectivity over the related ERa receptor. One of these, compound 11, had an interesting binding conformation determined by X-ray and represents an excellent starting point in the quest for further selective ERb agonists.

- There has been significant interest in the potential therapeutic benefit of selective ERb agonists to treat a variety of conditions including endometriosis3 and inflammatory bowel disease

- The amino acid sequence of the ligand binding domains between ERa and ERb is very highly conserved with only minor differences; Leu384 and Met421 in ERa is replaced by Met336 and Ile373 in ERb. The overall molecule is shown here with the in ERb in blue to show their location.

1. The amines were either purchased commercially or made via addition of a primary amine to an epoxide as shown in Scheme

2. The compounds were tested as racemates and those of interest were separated by chiral HPLC. A wide range of analogues were prepared utilising the approach described.

This is an overall scene with the beta sheets in purple and the alpha helices in ball and stick figures

Here is another scene with a rainbow diagram description of the whole molecule

Further scenes will be put in regarding more in depth focus on the estrogen receptor

Overall Structure

- Secondary Structure

- Mostly alpha helices with only two beta strands on the outside of the receptor shown below with the apla helices showing pollar and non-polar parts of the chain. The beta sheets are shown in yellow in the second green scene

- , and

- Tertiary Structure

- Polar- Pink, Hydrophobic- Grey

- Surface groups (orange) vs. Buried groups (blue)

Binding Interactions

- Complexes were originally designed to form an interaction with the His475 through the tertiary hydroxyl group

- Instead, the hydroxyl group acts as a conformational lock which forms an internal hydrogen bond with the sulphonamide oxygen about 2.3 A apart.

- The sulphonamide oxygens pack against Met336 and the benzyl group at top of the pocket comes near His475 but does not form any coulombic interactions but Van der Waals interactions exist near the pocket.

- Complexes make H-bonding interactions not only with Arg346 and Glu305 but also His475

See Also

• [Estrogen Receptor]
• [1yy4]
• [1u3s]
• [1x78]
• [1qkn]

Credits

Introduction - Benjamin Homyak

Overall Structure - Marissa Burgess

Drug Binding Site - Soo Lim Park

References

1. ↑ Roberts LR, Armor D, Barker C, Bent A, Bess K, Brown A, Favor DA, Ellis D, Irving SL, MacKenny M, Phillips C, Pullen N, Stennett A, Strand L, Styles M. Sulfonamides as selective oestrogen receptor beta agonists. Bioorg Med Chem Lett. 2011 Oct 1;21(19):5680-3. Epub 2011 Aug 16. PMID:21885279 doi:10.1016/j.bmcl.2011.08.041