Fig 1.
(A) The ERRAT quality factors of PDE4 structure. (B) Ramachandran plot. The yellow region shows the allowed region while the white region shows the disallowed regions.
Fig 2.
The developed pharmacophore models.
(A) The pharmacophoric features shown in the protein pocket. (B) The receptor cavity along with the pharmacophoric features.
Table 1.
The pharmacophore hypothesis features along with scores and coordinates in the receptor cavity.
Table 2.
The hits generated during virtual screening, selected based on the phase screen scores.
Fig 3.
The molecular structures of the compounds selected based on the binding affinities.
Fig 4.
The binding interactions of hits with protein.
The hydrogen bonds are shown by green spheres, hydrophobic interactions are shown by magenta color, the purple lines show pi-sigma, while orange lines show the pi-sulfur interactions.
Fig 5.
The plausible binding modes of the selected compounds are represented with the sticks in the binding pocket of protein.
The orientation of the hits is also shown in the pocket separately. (A) D356-2630 (B) D356-2542 (C) 8525–0383 (D) C700-2058 (E) D359-0432 (F) G842-0420 (G) G289-0060 (H) 8525–0381 (I) 7752–0515 (J) F403-0203.
Table 3.
The docking scores, interacting residues and the hydrogen bond distances of the selected compounds with protein.
Table 4.
The predicted bioactivity scores of the selected compounds against different human receptors.
Table 5.
The ADMET and toxicity risks analysis of the selected hits.
Table 6.
The toxicity profiles of the selected hits.
Fig 6.
The RMSD protein along with selected hits calculated during simulation.
(A) D356-2630 (B) C700-2058 (C) G842-0420 (D) F403-0203.
Fig 7.
The residual flexibility of the complexes during simulation along with the loop regions with higher fluctuations.
(A) D356-2630 (B) C700-2058 (C) G842-0420 (D) F403-0203.
Fig 8.
The Protein-Ligand contacts generated during the 100 ns simulation.
(A) D356-2630 complex. B) C700-2058 complex. (C) G842-0420 complex. (D) F403-0203 complex. Green shows hydrogen bonding, purple shows hydrophobic interactions, and blue shows the water bridges.
Fig 9.
Principal component analysis of the selected complexes.
(A) D356-2630 B) C700-2058 (C) G842-0420 (D) F403-0203.
Fig 10.
PCA based free energy surface of the complex calculated during simulation.
(A) D356-2630 B) C700-2058 (C) G842-0420 (D) F403-0203.
Fig 11.
The comparison of binding free energy components in selected complexes.