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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

Binding energy correlation between experimental ΔGbind and LIE (Glide/Prime) ΔGbind (A) or LIE (Affinity/SA) ΔGbind (B).
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Figure 7: Binding energy correlation between experimental ΔGbind and LIE (Glide/Prime) ΔGbind (A) or LIE (Affinity/SA) ΔGbind (B).

Mentions: In order to validate the optimum docking conformations by a means that would consider the solvation and entropy effects, we employed the Linear Interaction Energy (LIE) method based on the Surface Generalized Born continuum solvation model [17]. The experimental ΔGbind values determined from the binding affinity data were compared with the estimated ΔGbind values obtained from the identified docking conformations. Fitting the estimated ΔGbind values from either the Glide/Prime conformations or the Affinity/SA conformations to their experimental ΔGbind values yielded the following LIE equations: for the Glide/Prime conformations, ΔGbind = 0.381<ΔUvdw> + 0.028 <ΔUelec> + 1.271 ΔSASA; and for the Affinity/SA conformations, ΔGbind = 0.348 <ΔUvdw> + 0.032 <ΔUelec> + 1.084 ΔSASA. For both conformations, the RMSD of <1.0 kcal/mol was obtained. Using these equations, the calculated ΔGbind values correlated well with the experimental ΔGbind values for compounds 1 through 6 (Fig. 7 and Table 2). The Jackknife correlation coefficient indicated that the Affinity/SA conformation derived LIE equation is more robust than the Glide/Prime conformation-derived LIE equation (Table 2). However, these data do not predict efficacy of ligand-induced conformational changes that may be required for biological activity.


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

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

Binding energy correlation between experimental ΔGbind and LIE (Glide/Prime) ΔGbind (A) or LIE (Affinity/SA) ΔGbind (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Binding energy correlation between experimental ΔGbind and LIE (Glide/Prime) ΔGbind (A) or LIE (Affinity/SA) ΔGbind (B).
Mentions: In order to validate the optimum docking conformations by a means that would consider the solvation and entropy effects, we employed the Linear Interaction Energy (LIE) method based on the Surface Generalized Born continuum solvation model [17]. The experimental ΔGbind values determined from the binding affinity data were compared with the estimated ΔGbind values obtained from the identified docking conformations. Fitting the estimated ΔGbind values from either the Glide/Prime conformations or the Affinity/SA conformations to their experimental ΔGbind values yielded the following LIE equations: for the Glide/Prime conformations, ΔGbind = 0.381<ΔUvdw> + 0.028 <ΔUelec> + 1.271 ΔSASA; and for the Affinity/SA conformations, ΔGbind = 0.348 <ΔUvdw> + 0.032 <ΔUelec> + 1.084 ΔSASA. For both conformations, the RMSD of <1.0 kcal/mol was obtained. Using these equations, the calculated ΔGbind values correlated well with the experimental ΔGbind values for compounds 1 through 6 (Fig. 7 and Table 2). The Jackknife correlation coefficient indicated that the Affinity/SA conformation derived LIE equation is more robust than the Glide/Prime conformation-derived LIE equation (Table 2). However, these data do not predict efficacy of ligand-induced conformational changes that may be required for biological activity.

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