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Binding mode prediction of conformationally restricted anandamide analogs within the CB1 receptor.

Padgett LW, Howlett AC, Shim JY - J Mol Signal (2008)

Bottom Line: To better understand the molecular interactions associated with binding and steric trigger mechanisms of receptor activation, a series of conformationally-restricted anandamide analogs having a wide range of affinity and efficacy were evaluated.A ligand possessing both high affinity and cannabinoid agonist efficacy was able to interact with both polar and hydrophobic interaction sites utilized by the potent and efficacious non-classical cannabinoid CP55940.In contrast, other analogs characterized by reduced affinity or efficacy exhibited less favorable interactions with those key residues.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience of Drug Abuse Research Program, Julius L, Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA. jyshim@nccu.edu.

ABSTRACT

Background: CB1 cannabinoid receptors are G-protein coupled receptors for endocannabinoids including anandamide and 2-arachidonoylglycerol. Because these arachidonic acid metabolites possess a 20-carbon polyene chain as the alkyl terminal moiety, they are highly flexible with the potential to adopt multiple biologically relevant conformations, particularly those in a bent form. To better understand the molecular interactions associated with binding and steric trigger mechanisms of receptor activation, a series of conformationally-restricted anandamide analogs having a wide range of affinity and efficacy were evaluated.

Results: A CB1 receptor model was constructed to include the extracellular loops, particularly extracellular loop 2 which possesses an internal disulfide linkage. Using both Glide (Schrödinger) and Affinity (Accelrys) docking programs, binding conformations of six anandamide analogs were identified that conform to rules applicable to the potent, efficacious and stereoselective non-classical cannabinoid CP55244. Calculated binding energies of the optimum structures from both procedures correlated well with the reported binding affinity values. The most potent and efficacious of the ligands adopted conformations characterized by interactions with both the helix-3 lysine and hydrophobic residues that interact with CP55244. The other five compounds formed fewer or less energetically favorable interactions with these critical residues. The flexibility of the tested anandamide analogs, measured by torsion angles around the benzene as well as the stretch between side chain moieties, could contribute to the differences in ability to interact with the CB1 receptor.

Conclusion: Analyses of multiple poses of conformationally-restricted anandamide analogs permitted identification of favored amino acid interactions within the CB1 receptor binding pocket. A ligand possessing both high affinity and cannabinoid agonist efficacy was able to interact with both polar and hydrophobic interaction sites utilized by the potent and efficacious non-classical cannabinoid CP55940. In contrast, other analogs characterized by reduced affinity or efficacy exhibited less favorable interactions with those key residues.

No MeSH data available.


Related in: MedlinePlus

Extracellular loop placement on the human CB1 receptor model illustrating key interacting residues among E1, E2, and E3.
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Figure 3: Extracellular loop placement on the human CB1 receptor model illustrating key interacting residues among E1, E2, and E3.

Mentions: It was revealed from the present CB1 receptor model that extracellular loop 2 (E2) was located in the central region of the receptor on the extracellular side and packed at the entrance of the transmembrane core region (Fig. 3). Molecular dynamics (MD) simulations showed that conformations of E1 and E3 were influenced by the positioning of E2 (data not shown), suggesting that the extracellular loop region can readily adopt protean conformational changes in a membrane environment. As shown in Fig. 3, there were several non-bonding interactions between E1, E2, and E3 that might contribute to domain stabilization among the extracellular loops. For example, two H-bonds (R182/Q261 and D184/K259) between E2 and E1 and one H-bond (D266/K370) between E2 and E3 were identified. E2 itself was stabilized not only by the disulfide bridge (C257/C264), but also by H-bond (E258/K259) and aromatic stacking (W255/F268) interactions. A closer examination revealed that E2 was stabilized by two well-developed H-bond networks: 1) D184(E1)-K259(E2)-E258(E2)-R186(TM3)-N256(E2)-P251(TM4); and 2) W255(E2)-D266(E2)-K370(TM6) (Fig. 3). In addition, there were several H-bonds between E2 and TM residues, including G254(E2)-L250(TM4), F268(E2)-D272(TM6), and Q261(E2)-K376(TM7), which would contribute to the loop stabilization.


Binding mode prediction of conformationally restricted anandamide analogs within the CB1 receptor.

Padgett LW, Howlett AC, Shim JY - J Mol Signal (2008)

Extracellular loop placement on the human CB1 receptor model illustrating key interacting residues among E1, E2, and E3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2289822&req=5

Figure 3: Extracellular loop placement on the human CB1 receptor model illustrating key interacting residues among E1, E2, and E3.
Mentions: It was revealed from the present CB1 receptor model that extracellular loop 2 (E2) was located in the central region of the receptor on the extracellular side and packed at the entrance of the transmembrane core region (Fig. 3). Molecular dynamics (MD) simulations showed that conformations of E1 and E3 were influenced by the positioning of E2 (data not shown), suggesting that the extracellular loop region can readily adopt protean conformational changes in a membrane environment. As shown in Fig. 3, there were several non-bonding interactions between E1, E2, and E3 that might contribute to domain stabilization among the extracellular loops. For example, two H-bonds (R182/Q261 and D184/K259) between E2 and E1 and one H-bond (D266/K370) between E2 and E3 were identified. E2 itself was stabilized not only by the disulfide bridge (C257/C264), but also by H-bond (E258/K259) and aromatic stacking (W255/F268) interactions. A closer examination revealed that E2 was stabilized by two well-developed H-bond networks: 1) D184(E1)-K259(E2)-E258(E2)-R186(TM3)-N256(E2)-P251(TM4); and 2) W255(E2)-D266(E2)-K370(TM6) (Fig. 3). In addition, there were several H-bonds between E2 and TM residues, including G254(E2)-L250(TM4), F268(E2)-D272(TM6), and Q261(E2)-K376(TM7), which would contribute to the loop stabilization.

Bottom Line: To better understand the molecular interactions associated with binding and steric trigger mechanisms of receptor activation, a series of conformationally-restricted anandamide analogs having a wide range of affinity and efficacy were evaluated.A ligand possessing both high affinity and cannabinoid agonist efficacy was able to interact with both polar and hydrophobic interaction sites utilized by the potent and efficacious non-classical cannabinoid CP55940.In contrast, other analogs characterized by reduced affinity or efficacy exhibited less favorable interactions with those key residues.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience of Drug Abuse Research Program, Julius L, Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA. jyshim@nccu.edu.

ABSTRACT

Background: CB1 cannabinoid receptors are G-protein coupled receptors for endocannabinoids including anandamide and 2-arachidonoylglycerol. Because these arachidonic acid metabolites possess a 20-carbon polyene chain as the alkyl terminal moiety, they are highly flexible with the potential to adopt multiple biologically relevant conformations, particularly those in a bent form. To better understand the molecular interactions associated with binding and steric trigger mechanisms of receptor activation, a series of conformationally-restricted anandamide analogs having a wide range of affinity and efficacy were evaluated.

Results: A CB1 receptor model was constructed to include the extracellular loops, particularly extracellular loop 2 which possesses an internal disulfide linkage. Using both Glide (Schrödinger) and Affinity (Accelrys) docking programs, binding conformations of six anandamide analogs were identified that conform to rules applicable to the potent, efficacious and stereoselective non-classical cannabinoid CP55244. Calculated binding energies of the optimum structures from both procedures correlated well with the reported binding affinity values. The most potent and efficacious of the ligands adopted conformations characterized by interactions with both the helix-3 lysine and hydrophobic residues that interact with CP55244. The other five compounds formed fewer or less energetically favorable interactions with these critical residues. The flexibility of the tested anandamide analogs, measured by torsion angles around the benzene as well as the stretch between side chain moieties, could contribute to the differences in ability to interact with the CB1 receptor.

Conclusion: Analyses of multiple poses of conformationally-restricted anandamide analogs permitted identification of favored amino acid interactions within the CB1 receptor binding pocket. A ligand possessing both high affinity and cannabinoid agonist efficacy was able to interact with both polar and hydrophobic interaction sites utilized by the potent and efficacious non-classical cannabinoid CP55940. In contrast, other analogs characterized by reduced affinity or efficacy exhibited less favorable interactions with those key residues.

No MeSH data available.


Related in: MedlinePlus