11 research outputs found

    The chemical structures of 17Ī²-estradiol (E<sub>2</sub>) and the 27 E<sub>2</sub> derivatives.

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    <p>The number of each carbon is labeled next to the atom in the E<sub>2</sub> structure. The names of the E<sub>2</sub> derivatives were shown in the upper left corner of each frame. The <i>RBA</i> values of the E<sub>2</sub> derivatives for ERĪ± and ERĪ² (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 E<sub>2</sub>) were shown in the lower right corner of each frame. The numbers were rounded to the nearest integer due to space constraint.</p

    Overlay of docked and crystal structures of ERĪ± LBD in complex with DES or E<sub>2</sub>. A

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    <p>. Superimposed structures of docking result and the crystal structure of ERĪ± LBD in complex with DES. The known crystal structure of ERĪ± 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 ERĪ± LBD was colored in magenta. <b>B</b>. Superimposed structures of docking result and the crystal structure of ERĪ± LBD in complex with E<sub>2</sub>. The known crystal structure of ERĪ± LBD in complex with E<sub>2</sub> (PDB code: 3ERE) was colored in yellow with E<sub>2</sub> colored in green. The docked E<sub>2</sub> was colored in orange and ERĪ± 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

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

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    <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. E<sub>2</sub> was colored in red; 1-methyl-E<sub>2</sub> and 4-Methyl-E<sub>2</sub> were colored in magenta; 2-OH-E<sub>2</sub> and 4-OH-E<sub>2</sub> were colored in green; 2-Br-E<sub>2</sub> and 4-Br-E<sub>2</sub> were colored in blue; 2-MeO-E<sub>2</sub> and 4-MeO-E<sub>2</sub> were colored in yellow. <b>A</b>. Overlay of all the <i>A</i>-ring derivatives. <b>B</b>. Overlay of E<sub>2</sub>, 1-methyl-E<sub>2</sub>, 2-MeO-E<sub>2</sub>, 2-OH-E<sub>2</sub> and 2-Br-E<sub>2</sub>. <b>C</b>. Overlay of E<sub>2</sub>, 4-methyl-E<sub>2</sub>, 4-MeO-E<sub>2</sub>, 4-OH-E<sub>2</sub> and 4-Br-E<sub>2</sub>.</p

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

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    <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. E<sub>2</sub> was colored in white. The ligands were shown in the following different colors: in <b>panel A</b>, 6Ī±-OH-E<sub>2</sub> (yellow), 6Ī²-OH-E<sub>2</sub> (orange), 6-keto-E<sub>2</sub> (pink), 6-dehydro-E<sub>2</sub> (red), 7-dehydro-E<sub>2</sub> (magenta), 9(11)-dehydro-E<sub>2</sub> (light blue), 11Ī±-OH-E<sub>2</sub> (purple) and 11 Ī²-OH-E<sub>2</sub> (green); in <b>panel B</b>, E<sub>1</sub> (magenta) estriol (16Ī±-OH-E<sub>2</sub>) (yellow), 16Ī²-OH-E<sub>2</sub> (orange), 16-keto-E<sub>2</sub> (pink), 17Ī±-OH-E<sub>2</sub> (red), 15Ī±-OH-E<sub>3</sub> (dark blue), 16Ī±-OH-E<sub>1</sub> (light blue), 16-keto-E<sub>1</sub> (purple), 16Ī±-OH-E<sub>2</sub>-17Ī± (brown), 16Ī²-OH-E<sub>2</sub>-17Ī± (grey).</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.

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    <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 yā€Š=ā€Šy<sub>0</sub>+ a/x.</p

    Hydrogen bond lengths (ƅ) and calculated van der Waals interaction energy (Ī”<i>E</i><sub>VDW</sub>, kcal/mol) and Coulomb interaction energy (Ī”<i>E</i><sub>Coulomb</sub>, kcal/mol) between estrogen derivatives and the ERĪ± and ERĪ² LBDs.

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    <p>Hydrogen bond lengths were quantified by measuring distances between the hydrogen atoms of the 3-hydroxyl group of estrogen derivatives and the O<sub>Īµ</sub> of ERĪ±-E353 or ERĪ²-E305, between the oxygen atoms of the 3-hydroxyl group of estrogen derivatives and the H<sub>Ī·</sub> of ERĪ±-R394 or ERĪ²-R346 and between the hydrogen atoms of 17-hydroxyl group of estrogen derivatives and N<sub>Ī“</sub> of ERĪ±-H524 or ERĪ²-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

    The overlay of the ligand-binding domains (LBDs) of ERĪ± and ERĪ².

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    <p>The protein structures were shown in cartoon and colored green and magenta for ERĪ± and ERĪ², respectively. E<sub>2</sub> molecules were shown in stick and colored blue and red in ERĪ± and ERĪ² LBD, respectively. Ī±-Helixes and Ī²-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

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

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    <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).

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

    Optimization of Non-ATP Competitive CDK/Cyclin Groove Inhibitors through REPLACE-Mediated Fragment Assembly

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    A major challenge in drug discovery is to develop and improve methods for targeting proteinā€“protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of proteinā€“protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit. Phenylheterocyclic isosteres replacing a critical chargeā€“charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structureā€“activity relationship of a bisĀ­(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds
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