Figure 1.
D2-like agonists.
Figure 2.
Superimposition of eticlopride re-docked with AD4.2 (cyan lines, A) and with Vina (magenta lines, B) toward eticlopride in complex with hD3 in the crystal structure 3PBL (green lines).
Figure 3.
Structure differentiation of hD3 and hD2L receptors simulated in membrane.
(A) Superimposition of hD3 (green cartoon) and hD2 (cyan cartoon) homology models before the refinement with simulation in membrane. (B) structural alignment of hD3 (green cartoon) and hD2 (cyan cartoon) receptors after 3 ns of MD simulation in membrane. (C) high correlation of hD3 and hD2 binding energies (Autodock Vina) of D2-like ligands from homology models without MD refinement. (D) low correlation of hD3 and hD2 binding energies (Autodock Vina) of D2-like ligands after MD refinement.
Figure 4.
Analysis of Root Mean Square Deviation of Cα atoms during molecular dynamics simulation.
RMSD respect to the starting structures, homology models, of hD3 (black squares) and hD2L (red circles) receptors.
Figure 5.
Ionic-look, structural marker of inactive state of G-protein Coupled Receptors.
(A) hD3 and (B) hD2L receptor.
Figure 6.
Evolution of binding pockets of hD3 and hD2L receptor after model refinement.
Pockets generated by Fpocket server are represented as colored clusters of spheres. Left panels represent hD3 (green ribbons) and right panels represent hD2L (cyan ribbons), before (A, B) and after (C, D) MD simulations. The red circles target the orthosteric binding pocket whereas the black circles highlight the allosteric binding pocket.
Table 1.
Deviations of Cα of residues belonging to the orthosteric binding pocket of optimized receptors in comparison with the starting models.
Table 2.
Predicted binding energy (Autodock 4.2) of D3 agonists towards hD3 and hD2 receptors. Experimental Ki (exp. Ki) with respective references are also shown.
Figure 7.
Correlation of predicted pKi and experimental pKi values.
Plots of D3 preferring agonists docked toward hD3 (A) and hD2L (B) receptors: a. dopamine; b. 7-OH-DPAT; c. 7-OH-PIPAT; d. pramipexole; e. quinpirole; f. ropinirole; g. rotigotine; h. PD 128,907; i. cis-8-OH-PBZI; j. ZINC45254546.
Table 3.
Ligand protein-interaction of D3–preferring receptor agonists docked with AD4.2.
Figure 8.
Pose of pramipexole (cyan lines) and compound ZINC45254546 (magenta lines, see also text) docked into hD3 (A) and hD2L (B) optimized receptor structures. H-bonds with Aspartate conserved residues are represented with yellow dashes.
Table 4.
Virtual Screening. Top scored compound ZINC45254546.