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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

Various conformations of arachidonyl derivatives in complex with proteins as found within the crystal structures of enzymes and binding proteins. The National Library of Medicine Protein Structure Data Base was searched for structures of arachidonic acid and its metabolites and analogs determined from X-ray crystal structures of known enzymes and binding proteins. (A) Arachidonic acid in complex with adipocyte lipid binding protein (1ADL), cyclooxygenase active site of COX-2 (ICVU), prostaglandin H2 synthase-1 (1DIY), and human serum albumin (1GNJ); (B) Methyl arachidonyl fluorophosphonate in complex with fatty acid amide hydrolase (1MT5); (C) 5,8,11,14,17-Eicosapentaenoic acid in complex with peroxisome proliferator activated receptor delta (3GWX) and prostaglandin endoperoxide H synthase-1 (1IGX).
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Figure 2: Various conformations of arachidonyl derivatives in complex with proteins as found within the crystal structures of enzymes and binding proteins. The National Library of Medicine Protein Structure Data Base was searched for structures of arachidonic acid and its metabolites and analogs determined from X-ray crystal structures of known enzymes and binding proteins. (A) Arachidonic acid in complex with adipocyte lipid binding protein (1ADL), cyclooxygenase active site of COX-2 (ICVU), prostaglandin H2 synthase-1 (1DIY), and human serum albumin (1GNJ); (B) Methyl arachidonyl fluorophosphonate in complex with fatty acid amide hydrolase (1MT5); (C) 5,8,11,14,17-Eicosapentaenoic acid in complex with peroxisome proliferator activated receptor delta (3GWX) and prostaglandin endoperoxide H synthase-1 (1IGX).

Mentions: One theory for binding of ligands to the cannabinoid receptor suggests that anandamide is in an extended conformation, with the ethanolamide head group near the extracellular surface of the receptor and the long hydrocarbon chain extending down into the core of the membrane [9]. Another possibility is that anandamide may exhibit a binding mode similar to that demonstrated for arachidonic acid, its biological precursor. Arachidonic acid is known to be a substrate for oxygenase enzymes such as cyclooxygenases (COXs) and arachidonate 15-lipoxygenase (15-LO). X-ray crystal structures of arachidonic acid in a complex with these proteins revealed that arachidonic acid formed many different bioactive conformations, as shown in Fig. 2. Many X-ray structures for arachidonic acid show a bent conformation when co-crystallized in adipocyte lipid binding protein (PDB code: 1ADL), cyclooxygenase COX-2 (PDB code: 1CVU), prostaglandin H2 synthase-1 (PDB code: 1DIY), and fatty acid amide hydrolase (FAAH) (PDB code: 1MT5). Modeling studies of arachidonic acid in these proteins predict structures that are also bent in conformation [10-12]. Thus, it is fair to say that there may not be a single bioactive conformation of anandamide, but several multiple conformations may exist, particularly those in a bent form.


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

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

Various conformations of arachidonyl derivatives in complex with proteins as found within the crystal structures of enzymes and binding proteins. The National Library of Medicine Protein Structure Data Base was searched for structures of arachidonic acid and its metabolites and analogs determined from X-ray crystal structures of known enzymes and binding proteins. (A) Arachidonic acid in complex with adipocyte lipid binding protein (1ADL), cyclooxygenase active site of COX-2 (ICVU), prostaglandin H2 synthase-1 (1DIY), and human serum albumin (1GNJ); (B) Methyl arachidonyl fluorophosphonate in complex with fatty acid amide hydrolase (1MT5); (C) 5,8,11,14,17-Eicosapentaenoic acid in complex with peroxisome proliferator activated receptor delta (3GWX) and prostaglandin endoperoxide H synthase-1 (1IGX).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Various conformations of arachidonyl derivatives in complex with proteins as found within the crystal structures of enzymes and binding proteins. The National Library of Medicine Protein Structure Data Base was searched for structures of arachidonic acid and its metabolites and analogs determined from X-ray crystal structures of known enzymes and binding proteins. (A) Arachidonic acid in complex with adipocyte lipid binding protein (1ADL), cyclooxygenase active site of COX-2 (ICVU), prostaglandin H2 synthase-1 (1DIY), and human serum albumin (1GNJ); (B) Methyl arachidonyl fluorophosphonate in complex with fatty acid amide hydrolase (1MT5); (C) 5,8,11,14,17-Eicosapentaenoic acid in complex with peroxisome proliferator activated receptor delta (3GWX) and prostaglandin endoperoxide H synthase-1 (1IGX).
Mentions: One theory for binding of ligands to the cannabinoid receptor suggests that anandamide is in an extended conformation, with the ethanolamide head group near the extracellular surface of the receptor and the long hydrocarbon chain extending down into the core of the membrane [9]. Another possibility is that anandamide may exhibit a binding mode similar to that demonstrated for arachidonic acid, its biological precursor. Arachidonic acid is known to be a substrate for oxygenase enzymes such as cyclooxygenases (COXs) and arachidonate 15-lipoxygenase (15-LO). X-ray crystal structures of arachidonic acid in a complex with these proteins revealed that arachidonic acid formed many different bioactive conformations, as shown in Fig. 2. Many X-ray structures for arachidonic acid show a bent conformation when co-crystallized in adipocyte lipid binding protein (PDB code: 1ADL), cyclooxygenase COX-2 (PDB code: 1CVU), prostaglandin H2 synthase-1 (PDB code: 1DIY), and fatty acid amide hydrolase (FAAH) (PDB code: 1MT5). Modeling studies of arachidonic acid in these proteins predict structures that are also bent in conformation [10-12]. Thus, it is fair to say that there may not be a single bioactive conformation of anandamide, but several multiple conformations may exist, particularly those in a bent form.

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