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

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

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 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

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

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

Overlay of docked and crystal structures of ERα LBD in complex with DES or E₂. A

<p>. Superimposed structures of docking result and the crystal structure of ERα LBD in complex with DES. The known crystal structure of ERα LBD in complex with DES (PDB code: 3ERD) was colored in yellow with DES colored in green. The docked DES was colored in orange and ERα LBD was colored in magenta. <b>B</b>. Superimposed structures of docking result and the crystal structure of ERα LBD in complex with E₂. The known crystal structure of ERα LBD in complex with E₂ (PDB code: 3ERE) was colored in yellow with E₂ colored in green. The docked E₂ was colored in orange and ERα LBD was colored in magenta. The green dashes indicated the hydrogen bonds formed. All the structures were shown in ball and stick. The atoms involved with hydrogen bond formation were colored according to the atom type, i.e. white for hydrogen, red for oxygen and blue for nitrogen. Hydrogen atoms in other amino acids were not shown.</p

The computed binding energy values (Δ<i>E</i>_binding) for the molecular docking study for the binding of myricetin, quercetin, chrysin or flavone with human COX I or COX II.

<p>The ligand-enzyme interaction energy value (Δ<i>E</i>_binding) was calculated using the following equation: Δ<i>E</i>_binding = <i>E</i>_complex−(<i>E</i>_COX+<i>E</i>_ligand), where <i>E</i>_complex was the potential energy for the complex of COX bound with the ligand, <i>E</i>_COX was the potential energy of the enzyme alone, and <i>E</i>_ligand was the potential energy for the ligand alone.</p