Elsevier

Steroids

Volume 62, Issue 3, March 1997, Pages 268-303
Steroids

Review
The estradiol pharmacophore: Ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site

https://doi.org/10.1016/S0039-128X(96)00242-5Get rights and content

Abstract

The accumulated knowledge on the binding of estradiol (E2) and its analogs and the results of affinity-labeling studies have been reviewed and are used herein to derive a binding site model for the estrogen receptor (ER). Estradiol is nonpolar and hydrophobic, except at its molecular termini. Most of its skeletal flexibility resides in the B-ring, and it probably binds in a low-energy conformation. The phenolic OH group in the A-ring contributes about 1.9 kcal/mol to the binding free energy and probably acts primarily as a hydrogen bond donor. The 17β-hydroxyl group in the D-ring contributes approximately 0.6 kcal/mol to the binding and probably acts as a hydrogen bond acceptor, either directly or via a water molecule. There also seems to be a degree of flexibility in the region of the receptor that encompasses the D-ring. The aromatic ring contributes about 1.5 kcal/mol, probably through weak polar interactions with receptor residues that contact the β-face of the steroid. The receptor seems to surround the ligand, so that all four rings contribute significantly to binding. Small hydrophobic substituents enhance binding affinity at positions 4, 12β, 14, and 16α; whereas, larger hydrophobic substituents are tolerated at positions 7α, 11β, and 17α. In general, the ER is intolerant of polar substituents. Based on E2 analogs bearing affinity-labeling groups, cysteine residue might be present in the binding site in the area of C-4, C-17α, and C-17β, and a lysine residue might be located near C-16. Models that represent the limits of deformability of the ligand binding site, the position of preformed pockets, and space occupied by the receptor are presented. The various elements in this model for the binding of steroidal estrogens by the estrogen receptor are consistent with evidence emerging from the crystal structures of related nuclear hormone receptor ligand complexes.

References (248)

  • R.D. Bindal et al.

    11β-Chloromethyl-[3H]estradiol-17β: A very high-affinity, reversible ligand for the estrogen receptor

    J Steroid Biochem

    (1987)
  • M. Salomonsson et al.

    Equilibrium hormone binding to human estrogen receptors in highly diluted cell extracts is noncooperative and has a Kd of approximately 10 pM

    J Steroid Biochem Molec Biol

    (1994)
  • R.L. Eckert et al.

    Physical properties of estrogen receptor complexes in MCF-7 human breast cancer cells

    J Biol Chem

    (1982)
  • G. Vollmer et al.

    Methyl and bromo derivatives of estradiol are agonistic ligands for the estrogen receptor of MCF-7 breast cancer cells

    J Steroid Biochem Molec Biol

    (1991)
  • T. Lövgren et al.

    Binding characteristics of estrone, estradiol, and estriol to the human myometrial receptor

    J Steroid Biochem

    (1978)
  • T. Ratajczak et al.

    The synthesis and study of some potential affinity labeling reagents for estrogen receptors

    Steroids

    (1981)
  • H.H. Keasling et al.

    The relationship between estrogenic action and chemical constitution in a group of azomethine derivatives

    J Am Pharm Assoc

    (1950)
  • T. Ojasoo et al.

    Correspondence factor analysis of steroid libraries

    Steroids

    (1995)
  • J. Delettré et al.

    Steroid flexibility and receptor specificity

    J Steroid Biochem

    (1980)
  • E.N. Baker et al.

    Hydrogen bonding in globular proteins

    Prog Biophys Molec Biol

    (1984)
  • G.A. Chernayaev et al.

    A series of optical, structural and isomeric analogs of estraidol: A comparative study of the biological activity and affinity to cytosol receptor of rabbit uterus

    J Steroid Biochem

    (1975)
  • K. Eik-Nes et al.

    The binding of steroids to proteins. I. Solubility determinations

    J Biol Chem

    (1954)
  • R. Breton et al.

    The structure of a complex of human 17β-hydroxysteroid dehydrogenase with estradiol adn NADP+ identifies two principal targets for the design of inhibitors

    Structures

    (1996)
  • S.G. Korenman

    Comparative binding affinity of estrogens and its relation to estrogenic potency

    Steroids

    (1969)
  • Y.C. Martin

    Advances in the methodology of quantitative drug design

    Drug Design

    (1979)
  • J.A. Ippolito et al.

    Hydrogen bond stereochemistry in protein structure and function

    J Mol Biol

    (1990)
  • N. Thanki et al.

    Distribution of water around amino acid residues in proteins

    J Mol Biol

    (1988)
  • W.L. Duax et al.

    Molecular details of receptor binding and hormonal action of steroids derived from X-ray crystallographic investigations

    J Steroid Biochem

    (1981)
  • J.A. Rupley et al.

    Protein hydration and function

    Adv Protein Chem

    (1991)
  • B. Busetta et al.

    Some hypotheses about interactions between estrogen and androgen and their possible receptors

    J Steroid Biochem

    (1977)
  • C. Djerassi

    The bitter pill

    Science

    (1989)
  • P.E. Belchetz

    Drug therapy: Hormonal treatment of postmenopausal women

    N Engl J Med

    (1994)
  • L.L.P. Simonsen

    Top 200 drugs of 1993: Price of average Rx up only 2.9%

    Pharm Times

    (1994)
  • T.L. Fevig et al.

    A short, stereoselective route to 16α-(substituted-alkyl)estradiol derivatives

    J Org Chem

    (1987)
  • B.S. Katzenellenbogen et al.

    Affinity labeling studies of estrogen receptors

  • J.A. Katzenellenbogen et al.

    Cytotoxic oestrogens and antioestrogens: Concepts, progress, and evaluation

  • E. von Angerer

    The Estrogen Receptor as a Target for Rational Drug Design

    (1995)
  • R.M. Evans

    The steroid and thyroid hormone receptor superfamily

    Science

    (1988)
  • S. Green et al.

    The oestrogen receptor: from perception to mechanism

  • H. Gronemeyer et al.

    Transcription Factors 3: Nuclear Receptors

  • F.J. Zeelen

    Medicinal Chemistry of Steroids

    (1990)
  • S. Koike et al.

    Molecular cloning and characterization of rat estrogen receptor cDNA

    Nucleic Acids Res

    (1987)
  • R. White et al.

    Structural organization and expression of the mouse estrogen receptor

    Mol Endocrinol

    (1987)
  • S. Green et al.

    Human oestrogen receptor cDNA: Sequence, expression and homology to v-erb-A

    Nature

    (1986)
  • G.L. Greene et al.

    Sequence and expression of human estrogen receptor complementary DNA

    Science

    (1986)
  • A. Krust et al.

    The chicken oestrogen receptor sequence: Homology with v-erbA and the human oestrogen and glucocorticoid receptors

    EMBO J

    (1986)
  • W. Bourguet et al.

    Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α

    Nature

    (1995)
  • J. Renaud et al.

    Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid

    Nature

    (1995)
  • R.L. Wagner et al.

    A structural role for hormone in the thyroid hormone receptor

    Nature

    (1995)
  • J.-M. Wurtz et al.

    A canonical structure for the ligand-binding domain of nuclear receptors

    Nature Struct Biol

    (1996)
  • Cited by (593)

    • Covalent ligands of nuclear receptors

      2023, European Journal of Medicinal Chemistry
    View all citing articles on Scopus
    View full text