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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

Side (A) and top (B) views of the overlay of the docking modes of CP55244 determined using Glide/Prime (in lavender), Affinity/SA (in cyan) and the previously published CP55244 docking mode (in white). The CB1 receptor helical backbone is represented in Cα trace format. TM1 through TM7 are colored in red, orange, yellow, green, cyan, blue and purple, and the extracellular loops are colored in magenta.
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Figure 4: Side (A) and top (B) views of the overlay of the docking modes of CP55244 determined using Glide/Prime (in lavender), Affinity/SA (in cyan) and the previously published CP55244 docking mode (in white). The CB1 receptor helical backbone is represented in Cα trace format. TM1 through TM7 are colored in red, orange, yellow, green, cyan, blue and purple, and the extracellular loops are colored in magenta.

Mentions: As shown in Fig. 4, the CP55244 docking mode determined by Glide/Prime overlapped quite well with the previously published CP55244 docking model that had been developed using Affinity[16]. As described in [16], the putative binding conformation of CP55244 was identified and supported by a highly significant correlation between affinity determined from radioligand binding studies and ligand-receptor interaction energies for over 30 non-classical cannabinoid agonist ligands. In both models, the phenolic hydroxyl interacted with K3.28 (192). There was strong aromatic stacking of the A-ring with F7.35(379) which are 4.7 Å apart. This residue had contributed the greatest interaction in the previously published model [16]. The C3 tail interacts with numerous residues within TM3 and TM6, as was previously observed [16].


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

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

Side (A) and top (B) views of the overlay of the docking modes of CP55244 determined using Glide/Prime (in lavender), Affinity/SA (in cyan) and the previously published CP55244 docking mode (in white). The CB1 receptor helical backbone is represented in Cα trace format. TM1 through TM7 are colored in red, orange, yellow, green, cyan, blue and purple, and the extracellular loops are colored in magenta.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Side (A) and top (B) views of the overlay of the docking modes of CP55244 determined using Glide/Prime (in lavender), Affinity/SA (in cyan) and the previously published CP55244 docking mode (in white). The CB1 receptor helical backbone is represented in Cα trace format. TM1 through TM7 are colored in red, orange, yellow, green, cyan, blue and purple, and the extracellular loops are colored in magenta.
Mentions: As shown in Fig. 4, the CP55244 docking mode determined by Glide/Prime overlapped quite well with the previously published CP55244 docking model that had been developed using Affinity[16]. As described in [16], the putative binding conformation of CP55244 was identified and supported by a highly significant correlation between affinity determined from radioligand binding studies and ligand-receptor interaction energies for over 30 non-classical cannabinoid agonist ligands. In both models, the phenolic hydroxyl interacted with K3.28 (192). There was strong aromatic stacking of the A-ring with F7.35(379) which are 4.7 Å apart. This residue had contributed the greatest interaction in the previously published model [16]. The C3 tail interacts with numerous residues within TM3 and TM6, as was previously observed [16].

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