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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

Structures of Endocannabinoids and CP55244. The structures of anandamide (N-arachidonylethanolamide), 2-arachidonoylglycerol (2-AG), nolandin ether (2-arachidonyl glyeryl ether, 2-AGE), and virodhamine (arachidonylethanolamine ester) are shown. The non-classical cannabinoid, CP55244 is depicted with the accepted numbering and ring nomenclature.
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Figure 1: Structures of Endocannabinoids and CP55244. The structures of anandamide (N-arachidonylethanolamide), 2-arachidonoylglycerol (2-AG), nolandin ether (2-arachidonyl glyeryl ether, 2-AGE), and virodhamine (arachidonylethanolamine ester) are shown. The non-classical cannabinoid, CP55244 is depicted with the accepted numbering and ring nomenclature.

Mentions: CB1 and CB2 cannabinoid receptors belong to the G-protein coupled receptor (GPCR) family. Members of this cell-surface receptor family are characterized by seven transmembrane (TM) helices connected by intra- and extracellular loops. Lipid ligands serve as the regulators of these receptors, and are collectively referred to as endocannabinoids. Anandamide (also known as N-arachidonylethanolamide) [1], 2-arachidonoylglycerol (2-AG) [2,3], 2-arachidonyl glyceryl ether (2-AGE or nolandin ether) [4], and virodhamine (arachidonyl ethanolamine ester) [5] (Fig. 1) have been reported to be endocannabinoids. A common feature of endocannabinoids is the long polyene hydrocarbon chain as the alkyl terminal moiety, which makes these compounds highly flexible with the potential to adopt many different binding conformations. Investigation of the bioactive conformation of anandamide can provide valuable insight into how endocannabinoids interact with the cannabinoid receptor and how their binding transfers the molecular signal to the coupled G-proteins. However, due to the conformational flexibility of anandamide, determination of the bioactive conformation within the CB1 receptor active site has been hampered. Although the binding mode of anandamide within the receptor remains to be determined, it has been demonstrated that anandamide is able to adopt quite different conformations in various media [6-8].


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

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

Structures of Endocannabinoids and CP55244. The structures of anandamide (N-arachidonylethanolamide), 2-arachidonoylglycerol (2-AG), nolandin ether (2-arachidonyl glyeryl ether, 2-AGE), and virodhamine (arachidonylethanolamine ester) are shown. The non-classical cannabinoid, CP55244 is depicted with the accepted numbering and ring nomenclature.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Structures of Endocannabinoids and CP55244. The structures of anandamide (N-arachidonylethanolamide), 2-arachidonoylglycerol (2-AG), nolandin ether (2-arachidonyl glyeryl ether, 2-AGE), and virodhamine (arachidonylethanolamine ester) are shown. The non-classical cannabinoid, CP55244 is depicted with the accepted numbering and ring nomenclature.
Mentions: CB1 and CB2 cannabinoid receptors belong to the G-protein coupled receptor (GPCR) family. Members of this cell-surface receptor family are characterized by seven transmembrane (TM) helices connected by intra- and extracellular loops. Lipid ligands serve as the regulators of these receptors, and are collectively referred to as endocannabinoids. Anandamide (also known as N-arachidonylethanolamide) [1], 2-arachidonoylglycerol (2-AG) [2,3], 2-arachidonyl glyceryl ether (2-AGE or nolandin ether) [4], and virodhamine (arachidonyl ethanolamine ester) [5] (Fig. 1) have been reported to be endocannabinoids. A common feature of endocannabinoids is the long polyene hydrocarbon chain as the alkyl terminal moiety, which makes these compounds highly flexible with the potential to adopt many different binding conformations. Investigation of the bioactive conformation of anandamide can provide valuable insight into how endocannabinoids interact with the cannabinoid receptor and how their binding transfers the molecular signal to the coupled G-proteins. However, due to the conformational flexibility of anandamide, determination of the bioactive conformation within the CB1 receptor active site has been hampered. Although the binding mode of anandamide within the receptor remains to be determined, it has been demonstrated that anandamide is able to adopt quite different conformations in various media [6-8].

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