Experimental and predicted GSK3β inhibitory activities (log(10³/IC₅₀)) of MCMs and NCMs using model CoMSIA-NCM-SHD.

a<p>Compounds <b>1</b> from reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102212#pone.0102212-Kuo1" target="_blank">[17]</a>, compounds <b>2a–2u</b> from reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102212#pone.0102212-Kozikowski1" target="_blank">[19]</a>, compounds <b>2v</b>–<b>2ba</b> and <b>5</b> from reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102212#pone.0102212-Gaisina1" target="_blank">[21]</a>, compounds <b>3</b> from reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102212#pone.0102212-Zhang2" target="_blank">[20]</a>, and compounds <b>4</b> from reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102212#pone.0102212-Zhang1" target="_blank">[18]</a>.</p>b<p>Predictions using model CoMSIA-NCM-SHD.</p>c<p>Compounds predicted in the test set.</p

Structures of MCMs (1, 3, and 4) and NCMs (2 and 5).

<p>Structures of MCMs (1, 3, and 4) and NCMs (2 and 5).</p

Scatter plot of the experimental activities versus predicted activities for model CoMSIA-NCM-SHD: (•) training-set predictions, (○) LOO cross-validated predictions, (×) test-set predictions.

<p>Scatter plot of the experimental activities versus predicted activities for model CoMSIA-NCM-SHD: (•) training-set predictions, (○) LOO cross-validated predictions, (×) test-set predictions.</p

Analysis of the propeller conformations of the docked maleimides.

<p>(A) Scheme of the propeller conformations. (B, C) Two views of the propeller conformations of MCMs. (D) Solvent-exposed substituents (at the left) and substituents near the DFG Asp200 (at the right) of NCMs showing the presence of indol-3-yl and benzofuran-3-yl groups at each position. (E) Dihedral angles Angle1 C4’-C3′-C3-C4 (close circles to the left) and Angle2 C4″-C3″-C4-C5 (open circles to the right) for each compound series (consider labels of the atoms as represented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102212#pone-0102212-g003" target="_blank">Figure 3A</a>). The same dihedral angles are represented for the crystallographic structure of <b>4e</b> (close and open squares, PDB code: 2OW3). The dashed lines box encloses the propeller conformations.</p

CoMSIA results using the best field combinations.^a

a<p>NC is the number of components from the PLS analysis; <i>R</i>² is the square of the correlation coefficient; <i>S</i> is the standard deviation of the regression; <i>F</i> is the Fischer ratio; and <i>Q</i>² and <i>S</i>_cv are the correlation coefficient and standard deviation, respectively, of the leave-one-out (LOO) cross-validation.</p

Conformational comparison of compound 4e from the crystal structures in GSK3β–inhibitor complex (inhibitor in yellow in online version, light gray in printed version) and from docking results (inhibitor in green in online version, dark gray in printed version).

<p>Conformational comparison of compound 4e from the crystal structures in GSK3β–inhibitor complex (inhibitor in yellow in online version, light gray in printed version) and from docking results (inhibitor in green in online version, dark gray in printed version).</p