Molecular Modeling of Human CCR2 Receptor within POPC Lipid Bilayer

Chemokine receptor 2 (CCR2), a G-protein coupled receptor (GPCR), is a critical target for several inflammatory and autoimmune diseases. The main restriction on designing desirable antagonists against CCR2 is the lack of appropriate crystal structure for this target. In the absence of such experimental data, computational methods triggering structure prediction provide a cost-effective option. Homology modeling has been widely used to explore GPCR structure. Within the present contribution, homology modeling, molecular docking and molecular dynamics (MD) simulation were applied to construct a reliable model for CCR2. In the present contribution, we docked INCB3344, one of the most potent CCR2 inhibitors, into the active site of the CCR2 protein. Subsequently, we studied the dynamic behavior of INCB3344-CCR2 complex in the presence of lipid membrane. Moreover; a detailed molecular mechanism of INCB3344 action has been proposed. It was revealed that Tyr120, His121, Tyr259 and Glu291 formed H-bond interactions with INCB3344 while residues such as Trp98, His202, Thr203 and Thr173 participated in hydrophobic interactions. As a consequence, a reliable homology model of CCR2 could be successfully developed on the basis of CCR5 crystallographic structure. Finally it was found that binding of INCB3344 led to the structural changes in CCR2 that provided more interaction sites. Results of this study may be useful to design further CCR2 inhibiting structures with the aim of developing desirable therapeutic agents.