Figure 1.
Chemical structures of PDE4 inhibitors in the training set.
Figure 2.
The best HypoGen pharmacophore model, Hypo1.
(A) Chemical features present in Hypo 1. (B) 3D spatial relationship and geometric parameters of Hypo1. Pharmacophore features are color-coded (cyan, hydrophobic; orange, ring aromatic; green, hydrogen bond acceptor). Pharmacophore features are color-coded: cyan, hydrophobic (HY); orange, ring aromatic (RA); green, hydrogen bond acceptor (HBA).
Figure 3.
(A) Mapping of the most active compound 1 on the best pharmacophore model, Hypo1. (B) Mapping of the least active compound 28 on the best pharmacophore model, Hypo1. Pharmacophore features are color-coded: cyan, hydrophobic (HY); orange, ring aromatic (RA); green, hydrogen bond acceptor (HBA).
Figure 4.
The correlation graph between experimental and estimated activity values based on Hypo1.
Figure 5.
Results of Fischer randomization test for 95% confidence level.
Figure 6.
The flowchart of procedure used in 3D QSAR pharmacophore modeling.
Figure 7.
Molecular docking experiments of PD00519 and compound 1 in the training set.
(A) Interaction between PDE4 and compound 1 as predicted by molecular docking. (B) Interaction between PDE4 and PD00519 as predicted by molecular docking. Active site residues are shown in stick form. Zn2+ and Mg2+ ions are shown in cyan and saddlebrown sphere, respectively. Hydrogen bond network with protein residues is represented in red dotted lines. Interaction network with metal ions is represented in cyan dotted lines. π-π stacking interaction is represented in green dotted lines. Compound 1 and PD00519 are color-coded: cyan – compound 1, yellow – PD00519.
Figure 8.
The positions of PD00519 and compound 1 as predicted by molecular docking.
(A) Molecular overlay of PD00519 and compound 1 shown at the active site of PDE4. (B) The docking positions of PD00519 and compound 1 in the crystal structure of PDE4. PD00519 and compound 1 are color-coded: yellow – PD00519, cyan – compound 1.
Figure 9.
Pharmacophore mapping of PD00519 and compound 1 as predicted by molecular docking.
Active site residues are shown in stick form. PD00519 and compound 1 are color-coded: green – PD00519, cyan – compound 1. Pharmacophore features are color-coded: cyan, hydrophobic (HY); orange, ring aromatic (RA); green, hydrogen bond acceptor (HBA).
Figure 10.
Pharmacophore mapping of twelve hit compounds based on the best pharmacophore model, Hypo1.
(A) PD00519. (B) GK03776. (C) BTB01176. (D) AW01131. (E) AA-768-32245030. (F) AA-504-32628026. (G) AA-516-12432156. (H) BTB01888. (I) BTB01889. (J) BTB01180. (K) AW00861. (L) AA-768-30891048. Pharmacophore features are color-coded: cyan, hydrophobic (HY); orange, ring aromatic (RA); green, hydrogen bond acceptor (HBA).
Figure 11.
Alignment of twelve hit compounds with the best pharmacophore model, Hypo1.
Pharmacophore features are color-coded: cyan, hydrophobic (HY); orange, ring aromatic (RA); green, hydrogen bond acceptor (HBA).