Estradiol

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Vitamin D3 and estradiol are essential hormones that are formed in the body from the same source cholesterol. Whereas vitamin D3 is required mainly for calcium regulation and bone formation, estradiol regulates the reproductive cycle in women and maintains female characteristics. Both hormones are involved in various other functions in the body and act through their respective receptors which belong to the nuclear receptor superfamily. This article discusses the major role of vitamin D3 and estradiol in disorders such as osteoporosis, cancer and calcium regulation. Their functional similarity may be due to their participation at different junctures of the same mechanistic pathway or else a crosstalk between the two hormones and their opposite receptors. This suggests the possibility of designing effective drugs that would interact with both vitamin D3 and estrogen receptors for the treatment of vitamin D3 and estrogen-dependent disorders.
Vitamin D3 and estradiol are essential hormones that are formed in the body from the same source cholesterol. Whereas vitamin D3 is required mainly for calcium regulation and bone formation, estradiol regulates the reproductive cycle in women and maintains female characteristics. Both hormones are involved in various other functions in the body and act through their respective receptors which belong to the nuclear receptor superfamily. This article discusses the major role of vitamin D3 and estradiol in disorders such as osteoporosis, cancer and calcium regulation. Their functional similarity may be due to their participation at different junctures of the same mechanistic pathway or else a crosstalk between the two hormones and their opposite receptors. This suggests the possibility of designing effective drugs that would interact with both vitamin D3 and estrogen receptors for the treatment of vitamin D3 and estrogen-dependent disorders.
-
 
+
{| border="1;width:100%; height:200px;style=text-align:center"
-
MMDB ID: 14139
+
|+'''Table I:'''
-
 
+
|-
-
PDB ID: 1QKT
+
! style="background:brown; color:white" |MMDB ID
-
 
+
! style="background:brown; color:white" |PDB ID  
-
MMDB ID: 14140
+
! style="background:brown; color:white" |Reference
-
 
+
|-
-
PDB ID: 1QKU
+
|14139
-
 
+
|1QKT
-
Reference: Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065
+
|Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065
-
The crystal structure of a triple cysteine to serine mutant ERalpha ligand-binding domain (LBD), complexed with estradiol, shows that despite the presence of a tightly bound agonist ligand, the protein exhibits an antagonist-like conformation, similar to that observed in raloxifen and 4-hydroxytamoxifen-bound structures....
+
|-
-
 
+
|14140
-
MMDB ID: 17807
+
|1QKU
-
 
+
|Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065
-
PDB ID: 1JGL
+
|-
-
 
+
|17807
-
Reference: Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694
+
|1JGL
-
The crystal structure of a Fab fragment of an anti-17beta-estradiol antibody 57-2 was determined in the absence and presence of the steroid ligand, 17beta-estradiol (E2), at 2.5 and 2.15-A resolutions, respectively. The antibody binds the steroid in a deep hydrophobic pocket formed at the interface between the variable domains....
+
|Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694
-
 
+
|-
-
MMDB ID: 18390
+
|18390
-
 
+
|1G50
-
PDB ID: 1G50
+
|Eiler S, Gangloff M, Duclaud S, Moras D, Ruff MOverexpression, purification, and crystal structure of native ER alpha LBDProtein Expr. Purif. v22, p.165-173
-
 
+
|-
-
Reference: Eiler S, Gangloff M, Duclaud S, Moras D, Ruff MOverexpression, purification, and crystal structure of native ER alpha LBDProtein Expr. Purif. v22, p.165-173
+
|18412
-
Several crystal structures of human estrogen receptor alpha ligand-binding domain (hERalpha LBD) complexed with agonist or antagonist molecules have previously been solved. The proteins had been modified in cysteine residues (carboxymethylation) or renatured in urea to circumvent aggregation and denaturation problems. In this work, high-level protein expression and purification together with crystallization screening procedure yielded high amounts of soluble protein without renaturation or modifications steps....
+
|1JNN
-
 
+
|Monnet C, Bettsworth F, Stura EA, Le Du MH, Menez R, Derrien L, Zinn-Justin S, Gilquin B, Sibai G, Battail-Poirot N, Jolivet M, Menez A, Arnaud M, Ducancel F, Charbonnier JBHighly specific anti-estradiol antibodies: structural characterisation and binding diversityJ. Mol. Biol. v315, p.699-712
-
MMDB ID: 18412
+
|-
-
 
+
|20338
-
PDB ID: 1JNN
+
|1GWR
-
 
+
|Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike ACInteraction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alphaJ. Biol. Chem. v277, p.21862-21868
-
Reference: Monnet C, Bettsworth F, Stura EA, Le Du MH, Menez R, Derrien L, Zinn-Justin S, Gilquin B, Sibai G, Battail-Poirot N, Jolivet M, Menez A, Arnaud M, Ducancel F, Charbonnier JBHighly specific anti-estradiol antibodies: structural characterisation and binding diversityJ. Mol. Biol. v315, p.699-712
+
|-
-
Subtle modulation of antibody-binding properties by protein engineering often lies with an accurate structural and energetic description of how an antigen is recognised. Thus, with the intent to increase the affinity and add a bias in favour of natural estradiol compared with its chemically modified immunogen, we have determined the crystal structure of two anti-estradiol monoclonal antibodies, 10G6D6 and 17E12E5....
+
|20905
-
 
+
|1LHU
-
MMDB ID: 20338
+
|Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YASteroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformationJ. Biol. Chem. v277, p.32086-32093
-
 
+
|-
-
PDB ID: 1GWR
+
|25056
-
 
+
|1PCG
-
Reference: Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike ACInteraction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alphaJ. Biol. Chem. v277, p.21862-21868
+
|Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AFHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactionsProc. Natl. Acad. Sci. U. S. A. v100, p.11273-11278
-
The activation function 2/ligand-dependent interaction between nuclear receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit distinct preferences for such motifs depending both on the bound ligand and on the NR box sequence. To better understand the structural basis of motif recognition, we characterized the interaction between estrogen receptor alpha and the NR box regions of the p160 coactivator TIF2....
+
|-
-
 
+
|35805
-
MMDB ID: 20905
+
| 2D06
-
 
+
|Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JLThe structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substratesJ. Biol. Chem. v280, p.41482-41486
-
PDB ID: 1LHU
+
|-
-
 
+
|43057
-
Reference: Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YASteroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformationJ. Biol. Chem. v277, p.32086-32093
+
|2J7X
-
The amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG) contains a single high affinity steroid-binding site. Crystal structures of this domain in complex with several different steroid ligands have revealed that estradiol occupies the SHBG steroid-binding site in an opposite orientation when compared with 5 alpha-dihydrotestosterone or C19 androgen metabolites (5 alpha-androstan-3 beta,17 beta-diol and 5 alpha-androstan-3 beta,17 alpha-diol) or the synthetic progestin levonorgestrel....
+
|Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5.
-
 
+
Pike ACW, Brzozowski AM, Hubbard RE, Walton J, Bonn T, - A, Thorsell G, Engstrom O, Ljunggren J, Gustaffson J-A, Carlquist M, 2006/10/17  
-
MMDB ID: 25056
+
|-
-
PDB ID: 1PCG
+
|47760
-
Reference: Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AFHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactionsProc. Natl. Acad. Sci. U. S. A. v100, p.11273-11278
+
|1A52
-
The interaction between nuclear receptors and coactivators provides an arena for testing whether protein-protein interactions may be inhibited by small molecule drug candidates. We provide evidence that a short cyclic peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor alpha....
+
|Tanenbaum DM, Wang Y, Williams SP, Sigler PBCrystallographic comparison of the estrogen and progesterone receptor's ligand binding domainsProc. Natl. Acad. Sci. U. S. A. v95, p.5998-6003
-
 
+
|-
-
MMDB ID: 35805
+
|47957
-
 
+
|1AQU
-
PDB ID: 2D06
+
|Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908
-
 
+
|-
-
Reference: Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JLThe structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substratesJ. Biol. Chem. v280, p.41482-41486
+
|49701
-
Human SULT1A1 belongs to the supergene family of sulfotransferases (SULTs) involved in the sulfonation of xeno- and endobiotics. The enzyme is also one of the SULTs responsible for metabolic activation of mutagenic and carcinogenic compounds and therefore is implicated in various cancer forms. Further, it is not well understood how substrate inhibition takes place with rigid fused multiring substrates such as 17beta-estradiol (E2) at high substrate concentrations when subcellular fractions or recombinant enzymes are used....
+
|1IOL
-
 
+
|Azzi A, Rehse PH, Zhu DW, Campbell RL, Labrie F, Lin SXCrystal structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase complexed with 17 beta-estradiolNat. Struct. Biol. v3, p.665-668
-
MMDB ID: 43057
+
|-
-
 
+
|55024
-
PDB ID: 2J7X
+
|1A27
-
 
+
|Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
-
Description Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5.
+
|-
-
Deposition: Pike ACW, Brzozowski AM, Hubbard RE, Walton J, Bonn T, - A, Thorsell G, Engstrom O, Ljunggren J, Gustaffson J-A, Carlquist M, 2006/10/17  
+
|56114
-
 
+
|1FDS
-
MMDB ID: 47760
+
|Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
-
 
+
|-
-
PDB ID: 1A52
+
|56115
-
 
+
|1FDT
-
Reference: Tanenbaum DM, Wang Y, Williams SP, Sigler PBCrystallographic comparison of the estrogen and progesterone receptor's ligand binding domainsProc. Natl. Acad. Sci. U. S. A. v95, p.5998-6003
+
|Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
-
The 2.8-A crystal structure of the complex formed by estradiol and the human estrogen receptor-alpha ligand binding domain (hERalphaLBD) is described and compared with the recently reported structure of the progesterone complex of the human progesterone receptor ligand binding domain, as well as with similar structures of steroid/nuclear receptor LBDs solved elsewhere....
+
|-
-
 
+
|56116
-
MMDB ID: 47957
+
|1FDW
-
 
+
|Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
-
PDB ID: 1AQU
+
|-
-
 
+
|60515
-
Reference: Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908
+
|2OCF
-
The structure of estrogen sulphotransferase has been solved in the presence of inactive cofactor PAP and substrate 17 beta-estradiol. This structure reveals structural similarities between cytosolic sulphotransferases and nucleotide kinases.
+
|Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20  
-
 
+
|-
-
MMDB ID: 49701
+
|8897
-
 
+
|1ERE
-
PDB ID: 1IOL
+
|-
-
 
+
|Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist MMolecular basis of agonism and antagonism in the oestrogen receptorNature v389, p.753-758
-
Reference: Azzi A, Rehse PH, Zhu DW, Campbell RL, Labrie F, Lin SXCrystal structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase complexed with 17 beta-estradiolNat. Struct. Biol. v3, p.665-668
+
|-
-
 
+
|}
-
MMDB ID: 55024
+
{| border="1;width:100%; height:200px;style=text-align:center"
-
 
+
|+'''Table I:'''
-
PDB ID: 1A27
+
|-
-
 
+
! style="background:brown; color:white" |Physical Property
-
Reference: Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
+
! style="background:brown; color:white" |Value
-
Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes....
+
! style="background:brown; color:white" |Units  
-
 
+
! style="background:brown; color:white" |Temp (deg C)
-
MMDB ID: 56114
+
! style="background:brown; color:white" |Source
-
 
+
|-
-
PDB ID: 1FDS
+
|Melting Point
-
 
+
|178.5
-
Reference: Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
+
|deg C
-
BACKGROUND: The steroid hormone 17beta-estradiol is important in the genesis and development of human breast cancer. Its intracellular concentration is regulated by 17beta-hydroxysteroid dehydrogenase, which catalyzes the reversible reduction of estrone to 17beta-estradiol. This enzyme is thus an important target for inhibitor design....
+
| 
-
 
+
|EXP
-
MMDB ID: 56115
+
|-
-
 
+
|log P (octanol-water)
-
PDB ID: 1FDT
+
|4.01 (none)  
-
 
+
|
-
Reference: Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
+
|  
-
BACKGROUND: The steroid hormone 17beta-estradiol is important in the genesis and development of human breast cancer. Its intracellular concentration is regulated by 17beta-hydroxysteroid dehydrogenase, which catalyzes the reversible reduction of estrone to 17beta-estradiol. This enzyme is thus an important target for inhibitor design....
+
|EXP
-
 
+
|-
-
MMDB ID: 56116
+
|Water Solubility
-
 
+
|3.6
-
PDB ID: 1FDW
+
|mg/L
-
 
+
|27
-
Reference: Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
+
|EXP
-
Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes....
+
|-
-
 
+
|Vapor Pressure
-
MMDB ID: 60515
+
|1.26E-08
-
 
+
|mm Hg
-
PDB ID: 2OCF
+
|25
-
 
+
|EST
-
Description Human Estrogen Receptor Alpha Ligand-Binding Domain In Complex With Estradiol And The E2#23 Fn3 Monobody.
+
|-
-
Deposition: Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20  
+
|Henry's Law Constant
-
 
+
|3.64E-11
-
MMDB ID: 8897
+
|atm-m3/mole
-
 
+
|25
-
PDB ID: 1ERE
+
|EST
-
 
+
|-
-
Reference: Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist MMolecular basis of agonism and antagonism in the oestrogen receptorNature v389, p.753-758
+
|Atmospheric OH Rate Constant
-
Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes....
+
|1.23E-10
-
 
+
|cm3/molecule-sec
-
Physical Property Value Units Temp (deg C) Source
+
|25
-
Melting Point 178.5 deg C   EXP
+
|EST
-
log P (octanol-water) 4.01 (none)   EXP
+
|-
-
Water Solubility 3.6 mg/L 27 EXP
+
|}
-
Vapor Pressure 1.26E-08 mm Hg 25 EST
+
{| border="1;width:100%; height:200px;style=text-align:center"
-
Henry's Law Constant 3.64E-11 atm-m3/mole 25 EST
+
|+'''Table I:'''
-
Atmospheric OH Rate Constant 1.23E-10 cm3/molecule-sec 25 EST
+
|-
-
 
+
! style="background:brown; color:white" |Organism  
-
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
+
! style="background:brown; color:white" |Test Type
-
rat LD subcutaneous > 300mg/kg (300mg/kg)   Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.
+
! style="background:brown; color:white" |Route
 +
! style="background:brown; color:white" |Reported Dose (Normalized Dose)
 +
! style="background:brown; color:white" |Effect
 +
! style="background:brown; color:white" |Source
 +
|-
 +
|rat
 +
|LD
 +
|subcutaneous
 +
|> 300mg/kg (300mg/kg)  
 +
|  
 +
|Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.
 +
|-
 +
|}
'''Lipinski’s “Rule of Five” Prediction for a Compound’s ABSORPTION OR PERMEABILITY PROPERTIES'''
'''Lipinski’s “Rule of Five” Prediction for a Compound’s ABSORPTION OR PERMEABILITY PROPERTIES'''
Line 203: Line 215:
|POOR
|POOR
|-
|-
 +
|}

Revision as of 05:58, 24 October 2008

Estradiol

PUBCHEM (5757)

Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.

Therapeutic Indications

  • Menopause
  • Osteoporosis

KEGG Database(C00951,D00105) Pathway Androgen and estrogen metabolism Prostate cancer

NEXT BIO Database

Drug Type: Small Molecule; Approved; Investigational

Pharmacology: Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level.

Mechanism of Action: Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Indication: For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).

Half Life: 36 hours


Reference Article Ref1 Virtual and biomolecular screening converge on a selective agonist for GPR30

Cristian G Bologa1,7, Chetana M Revankar2,3,7, Susan M Young3, Bruce S Edwards3,4, Jeffrey B Arterburn5, Alexander S Kiselyov6, Matthew A Parker6, Sergey E Tkachenko6, Nikolay P Savchuck6, Larry A Sklar3,4, Tudor I Oprea1 & Eric R Prossnitz2,3

Estrogen is a hormone critical in the development, normal physiology and pathophysiology1 of numerous human tissues2. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand–activated family of transcription factors3. We have recently shown that the seven-transmembrane G protein–coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways4. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.

Ref2 Drugs Fut 2006, 31(1): 65 ISSN 0377-8282 Copyright 2006 Prous Science CCC: 0377-8282 DOI: 10.1358/dof.2006.031.01.959122

Structure-function similarity between vitamin D3 and estrogens: Scope for effective drug design for vitamin D3 and estrogen dependent disorders Ray, S., Gupta, A.

Vitamin D3 and estradiol are essential hormones that are formed in the body from the same source cholesterol. Whereas vitamin D3 is required mainly for calcium regulation and bone formation, estradiol regulates the reproductive cycle in women and maintains female characteristics. Both hormones are involved in various other functions in the body and act through their respective receptors which belong to the nuclear receptor superfamily. This article discusses the major role of vitamin D3 and estradiol in disorders such as osteoporosis, cancer and calcium regulation. Their functional similarity may be due to their participation at different junctures of the same mechanistic pathway or else a crosstalk between the two hormones and their opposite receptors. This suggests the possibility of designing effective drugs that would interact with both vitamin D3 and estrogen receptors for the treatment of vitamin D3 and estrogen-dependent disorders.

Table I:
MMDB ID PDB ID Reference
14139 1QKT Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065
14140 1QKU Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065
17807 1JGL Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694
18390 1G50 Eiler S, Gangloff M, Duclaud S, Moras D, Ruff MOverexpression, purification, and crystal structure of native ER alpha LBDProtein Expr. Purif. v22, p.165-173
18412 1JNN Monnet C, Bettsworth F, Stura EA, Le Du MH, Menez R, Derrien L, Zinn-Justin S, Gilquin B, Sibai G, Battail-Poirot N, Jolivet M, Menez A, Arnaud M, Ducancel F, Charbonnier JBHighly specific anti-estradiol antibodies: structural characterisation and binding diversityJ. Mol. Biol. v315, p.699-712
20338 1GWR Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike ACInteraction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alphaJ. Biol. Chem. v277, p.21862-21868
20905 1LHU Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YASteroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformationJ. Biol. Chem. v277, p.32086-32093
25056 1PCG Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AFHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactionsProc. Natl. Acad. Sci. U. S. A. v100, p.11273-11278
35805 2D06 Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JLThe structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substratesJ. Biol. Chem. v280, p.41482-41486
43057 2J7X Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5.

Pike ACW, Brzozowski AM, Hubbard RE, Walton J, Bonn T, - A, Thorsell G, Engstrom O, Ljunggren J, Gustaffson J-A, Carlquist M, 2006/10/17

47760 1A52 Tanenbaum DM, Wang Y, Williams SP, Sigler PBCrystallographic comparison of the estrogen and progesterone receptor's ligand binding domainsProc. Natl. Acad. Sci. U. S. A. v95, p.5998-6003
47957 1AQU Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908
49701 1IOL Azzi A, Rehse PH, Zhu DW, Campbell RL, Labrie F, Lin SXCrystal structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase complexed with 17 beta-estradiolNat. Struct. Biol. v3, p.665-668
55024 1A27 Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
56114 1FDS Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
56115 1FDT Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
56116 1FDW Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
60515 2OCF Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20
8897 1ERE
Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist MMolecular basis of agonism and antagonism in the oestrogen receptorNature v389, p.753-758
Table I:
Physical Property Value Units Temp (deg C) Source
Melting Point 178.5 deg C EXP
log P (octanol-water) 4.01 (none) EXP
Water Solubility 3.6 mg/L 27 EXP
Vapor Pressure 1.26E-08 mm Hg 25 EST
Henry's Law Constant 3.64E-11 atm-m3/mole 25 EST
Atmospheric OH Rate Constant 1.23E-10 cm3/molecule-sec 25 EST
Table I:
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
rat LD subcutaneous > 300mg/kg (300mg/kg) Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.

Lipinski’s “Rule of Five” Prediction for a Compound’s ABSORPTION OR PERMEABILITY PROPERTIES

Table I:
4 3 2 1 0
GOOD INDETERMINATE INDETERMINATE INDETERMINATE POOR
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