The overlay of the ligand-binding domains (LBDs) of ERα and ERβ.

<p>The protein structures were shown in cartoon and colored green and magenta for ERα and ERβ, respectively. E₂ molecules were shown in stick and colored blue and red in ERα and ERβ LBD, respectively. α-Helixes and β-sheets in the ER LBDs are labeled according to references <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074615#pone.0074615-Brzozowski1" target="_blank">[14]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074615#pone.0074615-Shiau1" target="_blank">[16]</a>. Helix 2 structures are missing in both <i>X</i>-ray structures.</p

Relationship between the correlation coefficient <i>r</i> and <i>x</i>/<i>y</i> for the estrogen derivatives in Table 1.

<p>For each <i>x</i>/<i>y</i> value, the total binding energy was calculated according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074615#pone.0074615.e003" target="_blank">equation (3</a>) and the correlation coefficient <i>r</i> value is calculated by correlating the total binding energy for each chemical with its log<i>RBA</i>. The <i>x</i>/<i>y</i> value is shown in log scale.</p

The chemical structures of 17β-estradiol (E₂) and the 27 E₂ derivatives.

<p>The number of each carbon is labeled next to the atom in the E₂ structure. The names of the E₂ derivatives were shown in the upper left corner of each frame. The <i>RBA</i> values of the E₂ derivatives for ERα and ERβ (data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074615#pone-0074615-t001" target="_blank"><b>Table 1</b></a> as % of <i>RBA</i> of E₂) were shown in the lower right corner of each frame. The numbers were rounded to the nearest integer due to space constraint.</p

Correlation of hydrogen bond length and log<i>RBA</i> of <i>A</i>-ring and <i>B</i>/<i>C</i>-ring derivatives.

<p>The hydrogen bond length data were shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074615#pone-0074615-t001" target="_blank"><b>Table 1</b></a>. The amino acids shown in the up right corner of each indicated that the hydrogen bonds were formed between 3-hydroxyl groups of the <i>A</i>-ring or <i>B</i>/<i>C</i>-ring derivatives and this specific amino acid in the binding pocket. The curve regression was performed according to the Inverse First Order equation y = y₀+ a/x.</p

Hydrogen bond lengths (Å) and calculated van der Waals interaction energy (Δ<i>E</i>_VDW, kcal/mol) and Coulomb interaction energy (Δ<i>E</i>_Coulomb, kcal/mol) between estrogen derivatives and the ERα and ERβ LBDs.

<p>Hydrogen bond lengths were quantified by measuring distances between the hydrogen atoms of the 3-hydroxyl group of estrogen derivatives and the O_ε of ERα-E353 or ERβ-E305, between the oxygen atoms of the 3-hydroxyl group of estrogen derivatives and the H_η of ERα-R394 or ERβ-R346 and between the hydrogen atoms of 17-hydroxyl group of estrogen derivatives and N_δ of ERα-H524 or ERβ-H475. For the <i>D</i>-ring derivatives, two hydrogen bond lengths were listed. The first is formed by hydrogen atoms of 17-hydroxyl groups and the second is formed by hydrogen atoms of 16-hydroxyl groups. Relative binding affinity (<i>RBA</i>) was also listed for comparison.</p

Schematic depiction of the catalysis and inactivation mechanism of COX enzymes and their interaction with bioflavonoids.

<p>PPIX is for protoporphorin IX. Quercetin structure is shown as a representative bioactive bioflavonoid. Events in the peroxidase cycle are labeled with numbers to denote the sequence of occurrence.</p

Correlation between log<i>RBA</i> and binding energy calculated with equation (1) and data in Table 1.

<p>The correlation coefficient <i>r</i> value is shown in the figure.</p

Summary of current 3D structures of ERs in complex with various ligands (listed according to the chronological order of the publications).

<p>Summary of current 3D structures of ERs in complex with various ligands (listed according to the chronological order of the publications).</p

Interactions of <i>A</i>-ring derivatives with ERα LBD determined by the molecular docking method.

<p>The green dashes indicate the hydrogen bonds formed. All the structures are shown in ball and stick. The amino acids were colored according to the atom type, i.e. green for carbon, red for oxygen, blue for nitrogen and white for hydrogen. Among the amino acids in the binding site, only E353, R394 and H524 were shown in this figure. E₂ was colored in red; 1-methyl-E₂ and 4-Methyl-E₂ were colored in magenta; 2-OH-E₂ and 4-OH-E₂ were colored in green; 2-Br-E₂ and 4-Br-E₂ were colored in blue; 2-MeO-E₂ and 4-MeO-E₂ were colored in yellow. <b>A</b>. Overlay of all the <i>A</i>-ring derivatives. <b>B</b>. Overlay of E₂, 1-methyl-E₂, 2-MeO-E₂, 2-OH-E₂ and 2-Br-E₂. <b>C</b>. Overlay of E₂, 4-methyl-E₂, 4-MeO-E₂, 4-OH-E₂ and 4-Br-E₂.</p

Interactions of <i>B</i>/<i>C</i>-ring (A) and <i>D</i>-ring derivatives (B) with ERα LBD determined by molecular docking.

<p>The green dashes indicate the hydrogen bonds formed. All the structures are shown in ball and stick. The amino acids were colored according to the atom type, i.e. green for carbon, red for oxygen, blue for nitrogen and white for hydrogen. Among the amino acids in the binding site, only E353, R394 and H524 are shown in this figure. E₂ was colored in white. The ligands were shown in the following different colors: in <b>panel A</b>, 6α-OH-E₂ (yellow), 6β-OH-E₂ (orange), 6-keto-E₂ (pink), 6-dehydro-E₂ (red), 7-dehydro-E₂ (magenta), 9(11)-dehydro-E₂ (light blue), 11α-OH-E₂ (purple) and 11 β-OH-E₂ (green); in <b>panel B</b>, E₁ (magenta) estriol (16α-OH-E₂) (yellow), 16β-OH-E₂ (orange), 16-keto-E₂ (pink), 17α-OH-E₂ (red), 15α-OH-E₃ (dark blue), 16α-OH-E₁ (light blue), 16-keto-E₁ (purple), 16α-OH-E₂-17α (brown), 16β-OH-E₂-17α (grey).</p