Fig 1.
Structure of PDE3A inhibitor series.
Common chemical scaffolds among the studied compounds are shown. Pyrazolopyridine and pyridazinone/pyrazolone moieties are highlighted in orange and magenta, respectively.
Fig 2.
Superposition of PDE3A model (pale orange) to the PDE3B crystal structure (cyan).
(a) Protein structure visualization presenting modeled loops (L1 and L2), and the location of metal and ligand binding site. (b) Comparison of PDE 3A/3B active sites; tertiary protein structure is shown in ribbons, relevant protein residues and water molecules are shown as thick tubes, magnesium ions are shown as van der Waals spheres, and ligands are shown in ball-and-stick representation; dotted lines indicate zero-order bonds, dashed black lines represent H-bonds, and cyan dashed lines indicate π-stacking interactions. Carbon coloring are: cyan and light blue for protein and ligand atoms in the PDE3B crystal, and pale orange and orange for protein and ligand atoms in the PDE3A model.
Fig 3.
Predicted binding modes of the studied compounds within the PDE3A binding site.
Each inhibitor series 1–5 is shown separately: set 1 in (a), set 2 in (b), set 3 in (c), set 4 in (d), and set 5 in (e). Ligands are shown in thin tubes representation with magenta carbons. Protein residues and metal-coordinating waters are displayed in thick tubes, and magnesium ions as van der Waals spheres. PDE3A residues are shown in gray, ligand binding residues in pale orange, and metal binding residues in light gray. Dashed black lines indicate H-bonds and cyan dashed lines denote π-stacking interactions. The tertiary structure is shown in white ribbons.
Table 1.
Averaged H-bond (first four columns) and π-stacking interaction (last two columns) distances for the ligand-PDE3A complexes extracted from molecular docking experiments.a.
Fig 4.
Template-based alignments of PDE3A inhibitors.
(a) Sets 2–4, (b) sets 1 and 5 in alignment PPA, and (c) sets 1 and 5 in PA. Pyrazolopyridine and pyridazinone/pyrazolone moieties are highlighted in orange and magenta, respectively.
Table 2.
Statistical information of FQSAR models.a.
Fig 5.
Scatter plots of the experimental vs. predicted activities for the best FQSAR models.
Plots are shown for alignments PPA, PA, and DA. (●) training, (○) LOO cross-validated, (×) test set predictions, and solid line is for x = y.
Fig 6.
FQSAR contour maps of the best models of PDE3A inhibitors for the PPA (a, b), PA (c, d) and DA (e) schemes. Compounds 1–2 (orange), 2-2b (purple), 4-6b (light green), and 5-3q (gray) are included as reference. In (e), the metal and ligand binding sites are shown for comparison following the same styling as Fig 3. Fields include steric (S), electrostatic (E), hydrophobic (H), H-bond acceptor (A) and donor (D). Images were generated using contour for positive and negative contribution values of 4.0 × 10−3 and −4.0 × 10−3, respectively.