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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

Comparison of the best position of the benzene and cis-2-butene moieties from MCSS with the Affinity/SA model of compound 1. Aromatic residues at or around the ligand binding pocket are represented including F3.25(189) and F7.35(379) identified as potentially important residues for aromatic stacking with compound 1.
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Figure 8: Comparison of the best position of the benzene and cis-2-butene moieties from MCSS with the Affinity/SA model of compound 1. Aromatic residues at or around the ligand binding pocket are represented including F3.25(189) and F7.35(379) identified as potentially important residues for aromatic stacking with compound 1.

Mentions: Aromatic stacking appears to be important for the ligand binding to CB1, as exemplified in all the potent ligand compounds that contain at least one aromatic ring (i.e., the A-ring of cannabinoids, and the indole ring of WIN55212 and other aminoalkylindole analogs) [18,19]. To further validate the docking position of the benzene ring in the tested compounds, we explored the best position of two key molecular fragments of compound 1 using the multiple copy simultaneous search (MCSS), a tool implemented in InsightII that predicts potential ligand binding sites. As shown in Fig. 8, the position of the benzene ring nearly overlaps with the aromatic ring of compound 1. The benzene ring in its lowest energy position was located such that many aromatic residues (including: F3.25(189), 5.80 Å; F2.61(174), 6.16 Å; F7.35(379), 8.06 Å) were potentially available to contribute to the aromatic-aromatic interaction within the binding pocket. The lowest energy position of the cis-2-butenyl moiety shared π-π interactions with three aromatic residues: F3.25(189), Y5.39(275), and F7.35(379), and the cis-2-butenyl moiety was quite close to the position of the vinyl moiety of compound 1 (Fig. 8). It can be postulated that the lowest energy position of the cis-2-butenyl moiety would be equivalent to the hydrophobic pocket that was proposed to be crucial in cannabinoid binding [18], at least for those compounds containing the unsaturated hydrocarbon side chain for which the π-π interaction would be the principal interaction [19].


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

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

Comparison of the best position of the benzene and cis-2-butene moieties from MCSS with the Affinity/SA model of compound 1. Aromatic residues at or around the ligand binding pocket are represented including F3.25(189) and F7.35(379) identified as potentially important residues for aromatic stacking with compound 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Comparison of the best position of the benzene and cis-2-butene moieties from MCSS with the Affinity/SA model of compound 1. Aromatic residues at or around the ligand binding pocket are represented including F3.25(189) and F7.35(379) identified as potentially important residues for aromatic stacking with compound 1.
Mentions: Aromatic stacking appears to be important for the ligand binding to CB1, as exemplified in all the potent ligand compounds that contain at least one aromatic ring (i.e., the A-ring of cannabinoids, and the indole ring of WIN55212 and other aminoalkylindole analogs) [18,19]. To further validate the docking position of the benzene ring in the tested compounds, we explored the best position of two key molecular fragments of compound 1 using the multiple copy simultaneous search (MCSS), a tool implemented in InsightII that predicts potential ligand binding sites. As shown in Fig. 8, the position of the benzene ring nearly overlaps with the aromatic ring of compound 1. The benzene ring in its lowest energy position was located such that many aromatic residues (including: F3.25(189), 5.80 Å; F2.61(174), 6.16 Å; F7.35(379), 8.06 Å) were potentially available to contribute to the aromatic-aromatic interaction within the binding pocket. The lowest energy position of the cis-2-butenyl moiety shared π-π interactions with three aromatic residues: F3.25(189), Y5.39(275), and F7.35(379), and the cis-2-butenyl moiety was quite close to the position of the vinyl moiety of compound 1 (Fig. 8). It can be postulated that the lowest energy position of the cis-2-butenyl moiety would be equivalent to the hydrophobic pocket that was proposed to be crucial in cannabinoid binding [18], at least for those compounds containing the unsaturated hydrocarbon side chain for which the π-π interaction would be the principal interaction [19].

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