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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

Ligand flexibility estimated from MD simulations for compounds 1, 2 and 6. The torsion angles around the aromatic ring, defined as τ 1(C = C-Car-Car) and τ 2(Car-Car-C = O), and the distance between the first carbon atom of the 1-heptenyl tail and the amide oxygen atom, defined as d [(C =)C...O(= C)] during a 5 ns MD simulation of compounds 1, 2, and 6. To resemble the highly hydrophobic environment within the binding pocket, the dielectric constant ε of 4.0 was used for the electrostatic interaction energy.
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Figure 9: Ligand flexibility estimated from MD simulations for compounds 1, 2 and 6. The torsion angles around the aromatic ring, defined as τ 1(C = C-Car-Car) and τ 2(Car-Car-C = O), and the distance between the first carbon atom of the 1-heptenyl tail and the amide oxygen atom, defined as d [(C =)C...O(= C)] during a 5 ns MD simulation of compounds 1, 2, and 6. To resemble the highly hydrophobic environment within the binding pocket, the dielectric constant ε of 4.0 was used for the electrostatic interaction energy.

Mentions: In studies to explore the flexibility of the conformationally-restricted anandamide analogs, we examined torsion angles around the aromatic ring, defined as τ1(C = C-Car-Car) and τ 2(Car-Car-C = O) during a 5 ns MD simulation of compounds 1, 2, and 6 (Fig. 9). It was assumed that the τ 1 torsion angle would indicate the flexibility of the 1-heptenyl tail of the ligand, while the τ 2 torsion angle would indicate the flexibility of the polar amide moiety of the ligand. As shown by the torsion angle of τ 1, compounds 1 and 2 appeared to be quite flexible around the aromatic ring. In contrast, compound 6 appeared to be much less flexible as indicated by having only two predominant orientations, around 120 and -120 degrees, respectively. The less flexible τ 1 torsion angle of compound 6 would lead to poor binding interaction with the hydrophobic binding pocket residues. Interestingly, compound 6 showed quite diverse τ 2 torsion angle values, comparable to those of compounds 1 and 2, suggesting that the polar amide moiety exhibited great flexibility in the molecules of this series, and could occupy alternative positions within the binding pocket.


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

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

Ligand flexibility estimated from MD simulations for compounds 1, 2 and 6. The torsion angles around the aromatic ring, defined as τ 1(C = C-Car-Car) and τ 2(Car-Car-C = O), and the distance between the first carbon atom of the 1-heptenyl tail and the amide oxygen atom, defined as d [(C =)C...O(= C)] during a 5 ns MD simulation of compounds 1, 2, and 6. To resemble the highly hydrophobic environment within the binding pocket, the dielectric constant ε of 4.0 was used for the electrostatic interaction energy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Ligand flexibility estimated from MD simulations for compounds 1, 2 and 6. The torsion angles around the aromatic ring, defined as τ 1(C = C-Car-Car) and τ 2(Car-Car-C = O), and the distance between the first carbon atom of the 1-heptenyl tail and the amide oxygen atom, defined as d [(C =)C...O(= C)] during a 5 ns MD simulation of compounds 1, 2, and 6. To resemble the highly hydrophobic environment within the binding pocket, the dielectric constant ε of 4.0 was used for the electrostatic interaction energy.
Mentions: In studies to explore the flexibility of the conformationally-restricted anandamide analogs, we examined torsion angles around the aromatic ring, defined as τ1(C = C-Car-Car) and τ 2(Car-Car-C = O) during a 5 ns MD simulation of compounds 1, 2, and 6 (Fig. 9). It was assumed that the τ 1 torsion angle would indicate the flexibility of the 1-heptenyl tail of the ligand, while the τ 2 torsion angle would indicate the flexibility of the polar amide moiety of the ligand. As shown by the torsion angle of τ 1, compounds 1 and 2 appeared to be quite flexible around the aromatic ring. In contrast, compound 6 appeared to be much less flexible as indicated by having only two predominant orientations, around 120 and -120 degrees, respectively. The less flexible τ 1 torsion angle of compound 6 would lead to poor binding interaction with the hydrophobic binding pocket residues. Interestingly, compound 6 showed quite diverse τ 2 torsion angle values, comparable to those of compounds 1 and 2, suggesting that the polar amide moiety exhibited great flexibility in the molecules of this series, and could occupy alternative positions within the binding pocket.

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