Editing Selective estrogen receptor modulator (section)

=== Binding modes ===
[[Image:Estradiol ring system.svg|thumb|left|class=skin-invert-image|The ABCD steroid ring system in 17β-estradiol.]]

The SERMs are known to feature four distinctive modes of binding to ER. One of those features are strong [[hydrogen bonds]] between the ligand and ERα's Arg-394 and Glu-353 that line the "A-ring pocket" and help the ligand to stay in ER's binding pocket. This is unlike 17β-estradiol which is hydrogen bonded to His-524 in the "D-ring pocket".<ref name="Nilsson_2011" /> Other distinctive bindings to the ligand-binding pocket are with a nearly planar "core" structure typically composed of a biaryl [[heterocycle]], equivalent to the A-ring and B-ring of 17β-estradiol, to the corresponding binding site; a bulky side chain from the [[biaryl]] structure, analogous to the B-ring of 17β-estradiol and finally a second side group that is the C- and D-ring equivalent and usually aromatic, fills the remainder volume of the ligand-binding pocket.<ref name="Vajdos_2007" />

The small differences between the two subtypes of ER have been used to develop subtype-selective ER modulators, but the high similarity between the two receptors make the development very challenging. Amino acids in the ligand-binding domains differ at two positions, Leu-384 and Met-421 in ERα and Met-336 and Ile-373 in ERβ, but they have similar hydrophobicity and occupying volumes. However, the shapes and the rotational barrier of the amino acid residues are not the same, leading to distinguish α- and β-face of the binding cavity between ERα and ERβ. This causes ERα-preferential-binding of ligand [[substituent]]s that are aligned downwards facing Met-336 while ligand substituents aligned upwards facing Met-336 are more likely to bind to ERβ. Another difference is in Val-392 in ERα, which is replaced by Met-344 in ERβ. ERβ's binding pocket volume is slightly smaller and the shape a bit different from ERα's. Many ERβ-selective ligands have a largely planar arrangement as the binding cavity of ERβ is slightly narrower than that of ERα, however, this by itself leads to modest selectivity. To attain strong selectivity, the ligand must place substituents very close to one or more of the amino acid differences between ERα and ERβ in order to create a strong repulsive force towards the other subtype receptor. In addition, the structure of the ligand must be rigid. Repulsive interactions may otherwise lead to the conformational change of the ligand and, therefore, create alternative binding modes.<ref name=Nilsson_2011 />

==== First-generation triphenylethylenes ====
Tamoxifen is converted by the liver [[cytochrome P450]] into the 4-hydroxytamoxifen<ref name=Rosano_2011 /> and is a more selective antagonist of the ERα subtype than ERβ.<ref name="Taneja_2006">{{cite journal | vauthors = Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA | title = Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy | journal = Expert Opinion on Investigational Drugs | volume = 15 | issue = 3 | pages = 293–305 | date = Mar 2006 | pmid = 16503765 | doi = 10.1517/13543784.15.3.293 | s2cid = 29510508 }}</ref> 4-hydroxytamoxifen binds to ERs within the same binding pocket that recognizes 17β-estradiol. The receptor recognition of 4-hydroxytamoxifen appears to be controlled by two structural features of 4-hydroxytamoxifen, the phenolic A ring, and the bulky side chain. The phenolic A ring forms hydrogen bonds to the side groups of ER's Arg-394, Glu-354 and to structurally conserved water. The bulky side chain, protruding from the binding cavity, displaces helix 12 from ligand-binding pocket to cover part of the coactivator binding pocket. The ER-4-hydroxytamoxifen complex formation recruits corepressors proteins. This leads to decreased DNA synthesis and inhibition of estrogen activity.<ref name=Rosano_2011 /> Clomifene and torimefene produce binding affinities similar to that of tamoxifen.<ref name="Fang_2001"/> Thus, these two drugs are more selective antagonists of the ERα subtype than ERβ.<ref name="Taneja_2006" />

==== Second-generation benzothiophenes ====
[[File:Raloxifene AnDring.png|thumb|385x385px|class=skin-invert-image|"A ring" (A) and "D ring" (D) marked in raloxifene.]]

Raloxifene, like 4-hydroxytamoxifen, binds to ERα with the hydroxyl group of its phenolic "A ring" through hydrogen bonds with Arg-394 and Glu-353. In addition to these bonds, raloxifene forms a second hydrogen bond to ER through the side group of His-524 because of the presence of a second hydroxyl group in the "D ring". This hydrogen bond is also unlike that between 17β-estradiol and His-524, as the [[imidazole ring]] of His-524 is rotated to counteract the difference of the oxygen position in raloxifene and in 17β-estradiol. Just like in 4-hydroxytamoxifen, the bulky side chain of raloxifene displaces helix 12.<ref name=Rosano_2011 />

==== Third-generation ====
Lasofoxifene interaction with ERα is typical of those between SERM-ERα such as a nearly planar [[topology]] (the tetrahydronapthalene carbocycle), hydrogen bonding with Arg-394 and Glu-353 and the phenyl side chains of lasofoxifene filling the C-ring and D-ring volume of the ligand-binding pocket. Lasofoxifene diverts helix 12 and prevents the binding of coactivator proteins with LXXLL motives. This is achieved by lasofoxifene occupying the space normally filled by Leu-540's side group and modulating the conformation of residues of helix 11 (His-524, Leu-525). Furthermore, lasofoxifene also directly interferes with helix 12 positioning by the drug's ethyl [[Pyrrolidine|pyrrolidine group]].<ref name=Rosano_2011 /> In vitro studies indicate that bazedoxifene competitively blocks 17β-estradiol by high and similar binding to both ERα and ERβ.<ref>{{cite book | editor-last1 = Sanchez | editor-first1 = Antonio Cano | editor-last2 = Calaf i Alsina | editor-first2 = Joaquin | editor-last3 = Dueñas-Díez | editor-first3 = José-Luis | title = Selective estrogen receptor modulators a new brand of multitarget drugs | date = 2006 | publisher = Springer | location = Berlin | isbn = 978-3-540-24227-7 | edition = 1st | pages = 282–3 | first = Santiago | last = Palacios | name-list-style = vanc | chapter = Endometrial Effects of SERMs | chapter-url = https://books.google.com/books?id=heJDAAAAQBAJ&q=bazedoxifene&pg=PA283 | doi = 10.1007/3-540-34742-9_11 }}</ref> Bazedoxifenes main binding domain consists of the 2-phenyl-3-methylindole and a hexamethylenamine ring at the side chain affected region.<ref name=Kung2009 />

Ospemifene is an oxidative deaminated metabolite of toremifene as has a similar binding to ER as toremifene and tamoxifen. The competitive binding to ERα and ERβ of the three metabolites 4-hydroxy Ospemifene, 4'-hydroxy Ospemifene and the 4-hydroxy-, side chain carboxylic acid Ospemifene is at least as high as the parent compound.<ref>{{cite web | publisher = The European Medicines Agency (EMA) | title = Senshio (ospemifene) | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002780/human_med_001837.jsp&mid=WC0b01ac058001d124 | access-date = 2015-11-02 | archive-date = 2018-06-20 | archive-url = https://web.archive.org/web/20180620173809/http://www.ema.europa.eu/ema//index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F002780%2Fhuman_med_001837.jsp&mid=WC0b01ac058001d124 | url-status = dead }}</ref>