page_title: Selective estrogen receptor modulator
section_title: Binding modes
hierarchical_section_title: Selective estrogen receptor modulator / Structure and function / Binding modes
caption_attribution_description: English: The ABCD steroid ring system in 17β-estradiol.
context_page_description: Selective estrogen receptor modulators are a class of drugs that act on the estrogen receptor. A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
context_section_description: 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". 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 (see figure 14), 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.
  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 substituents 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 conformational change of the ligand and, therefore, creating alternative binding modes.
caption: Figure 14: The ABCD steroid ring system in 17β-estradiol.
exif: {}