Figure 1.
Chemical structures of studied compounds using molecular docking.
CCR2 (Compound 2, 14, RS-504393 and Teijin), CCR5 (Maraviroc, SCH351125, TAK779 and Vicriviroc) and dual inhibitors (Compound 19).
Figure 2.
Sequence alignment of CCR2 (UniProtKB: P41597) and CCR5 (UniProtKB: P51681) with the CXCR4 (PDB ID; 3ODU) as template.
Star indicates identical amino acids; colon indicates similar amino acids and single dot designate almost similar amino acid.
Figure 3.
Potential energy plot of MD simulation.
(a) CCR2 and (b) CCR5 plot shows the variation in potential energy throughout the system for a period of 5 ns. Time is on the X-axis and the potential energy is on the Y-axis.
Figure 4.
Graphical representation of root mean square deviation (RMSD) plot.
RMSD for (a) CCR2 and (b) CCR5 Cα from the initial structures throughout the simulation of 5 ns as function of time.
Figure 5.
Ramachandran plot for the models after MD simulations.
(a) CCR2 and (b) CCR5 models are shown. The different color coding indicates most favored (red), generously allowed (dark yellow), additionally allowed (light yellow), and disallowed (white) regions.
Table 1.
Validation results of CCR2/CCR5 homology model before and after MDS.
Figure 6.
Top views of putative binding pockets after MD simulation for docking analyses.
(a) CCR2 transmembrane (TM) helices are shown in light green, whereas, constructed binding pocket residues were shown in smudge green sticks. All the TM regions are labeled by blue color on the top of helices. The binding pocket is also represented as transparent molecular surfaces. (b) CCR5 TM helices are shown in light brown color, whereas constructed binding pocket residues were shown in green sticks. Figure generated using Pymol program (http://www.pymol.org).
Figure 7.
Binding modes of CCR2 inhibitors.
TM helices are shown in pale green color, whereas constructed binding pocket residues were shown in cyan sticks. All the TM's are labeled by blue color on the top of helices. Docked ligands were shown in magenta color. (a) Docking model of Teijin shows key salt bridge interaction between pyrrolidine nitrogen and Glu291 by magenta dotted lines. Hydrogen bonding interactions are also observed with Tyr120 and His121. (b) RS-50323 shows salt bridge interaction between the linker nitrogen of the ligand and Glu291 which is indicated by magenta dotted lines. (c) Pyridyl derivative show crucial interaction between the hydrogen atom of the nitrogen and Glu291 which is indicated by magenta dotted lines. Hydrogen bonding interaction is also observed with Thr287. (d) Docking model of cyclohexyl derivatives identified crucial interaction between the hydrogen atom of nitrogen and Glu291 (magenta dotted lines). In addition, the same atom also hydrogen bonded with Tyr120.
Figure 8.
Binding modes of CCR5 inhibitors.
TM helices are shown in light brown color, whereas constructed binding pocket residues were shown in green sticks. All the TM's are labeled by blue color on the top of helices. Docked ligands were shown in yellow color. (a) Docked pose of Maraviroc in CCR5, the key salt bridge interaction with Glu283 is shown by magenta dotted line. Hydrogen bonds with Try37 and Tyr108 were shown in blue dotted lines. (b) Docking model of SCH-C show a key salt bridge interaction with Glu283 and represented by magenta dotted line. Hydrogen bond with Try37 is shown as blue dotted lines. Pyridine-N-Oxide ring of ligand interacts through strong aromatic π-stacking interaction with the Trp86 of CCR5. (c) TAK779 in CCR5 shows salt bridge interaction with Glu283 which is designated by magenta dotted line. Hydrogen bonds with Try37 and Thr167 are shown in blue dotted lines. Phenyl group of TAK779 docked deeply inside the cavity formed by Ile198, Tyr251, Asn252 and Leu255. (d) Docking model of Vicriviroc shows salt bridge interaction with Glu283 which is indicated by magenta dotted line. Pyrimidine ring of ligand interacts strongly via π-stacking interaction with Trp86. Tri-fluoro-phenyl of ligand is docked deeply into the cavity formed by Phe112, Ile198, Trp248, Tyr251, Asn252 and Leu255 residues.
Figure 9.
Docked models of dual inhibitor (compound 19).
(a) Docking model of compound 19 in CCR2 is shown in transparent surface. Salt bridge interaction of tertiary nitrogen with Glu291 is shown by dotted magenta lines, whereas hydrogen bond interaction of ligand-fluorine with Arg206 is shown by dotted cyan line. Side chains of interacting residues of CCR2 are shown in cap stick (cyan color), while ligand is shown in cap-stick with green color for carbon. (b) Binding mode of compound 19 in CCR5 cavity. Salt bridge interaction of tertiary nitrogen with Glu283 is shown by dotted magenta lines, whereas hydrogen bond interaction of pyridine nitrogen with Tyr108 is shown by dotted cyan line. Side chains of interacting residues of CCR5 are shown in cap stick (green color), while ligand is shown in cap-stick with cyan color for carbon. Trifluoromethyl group of ligand was docked into the hydrophobic cavity.