Ligand-specific homology modeling of human cannabinoid (CB1) receptor

Functional Activity and Switching of Novel Cannabinergic Ligands

“…254 More recent homology models form this pocket from I354(6.46), C355(6.47), W356(6.48), L359(6.51), L360(3.52) and M363(6.55) (Figure 3.19A). 249 Interestingly, mutations studies conducted on this hydrophobic pocket show that M363A(6.55) mutation greatly impacts binding affinity for HU-210 but has virtually no impact on THC which would suggest that this is an important residue for C-1′ substituted derivatives. 255 Due to the similar CB1 functional activity betwixt HU-210 and the KM series, it is hypothesized that the interactions of the lipophilic C-3 substituents are analogous (Figure 3.19B).…”

“…Dr. Chang, University of California at Riverdale, provided 4 models: "ACEA" -endocannabinoid model, "HU-210" -classical core model, "SR-141716A" -inverse agonist model and "WIN-55,212-2" -non-classical agonist model. 249 The KM series of compounds, I believe, adopt a similar binding mode within the LBP to that of HU-210, thus this was the model used for docking studies. Since it is a very flexible residue in the LBP, it can manifest conformations that allow it to hydrogen bond with either the C-1 hydroxyl, C-11 ("Northern") hydryoxyl, C-6 ("Southern") hydroxyl or even the benzochromene oxygen.…”

“…256 Stabilization of this interaction may lead to the specialized antagonists known as inverse agonists, and this is precisely how SR-141716A binds in some homology models -a parallel stacking between these two residues creates an aromatic micro domain for SR-141716A. 249 However, more recent homology models do not suggest this same binding mode for SR-141716A, and thus may indicate this is not as necessary an interaction. Second, interaction of W356(6.48) with the aryl ring of the KM Series draws the aryl ring more in contact with residues flanking W356(6.48), namely I354(6.46) and L359(6.51).…”

“…S383(7.35) can hydrogen bond with the C-11 ("Northern") hydroxyl 251 (if present) or the benzochromene oxygen 249,254 , but more importantly it helps to stabilize the LBP by maintaining the shape of the Trans-Membrane Helix 1-2-7 binding pocket. 251 The "Northern" hydroxyl group may, theoretically, H-bond with K192(3.28).…”

“…Dr. Chang provided 4 models: "ACEA" -to mimic the endocannabinoid binding, "HU-210" -to mimic the classical core binding, "SR-141716A" -to mimic the inverse agonist binding and "WIN-55,212-2" -to mimic the non-classical agonist binding. 249 The hexahydro series of compounds, being similar in form to that of HU-210, I believe adopt a similar binding mode within the LBP, thus this was the model used for docking studies.…”