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. 2022 Feb 11;23(4):2005.
doi: 10.3390/ijms23042005.

All-Atom Molecular Dynamics Investigations on the Interactions between D2 Subunit Dopamine Receptors and Three 11C-Labeled Radiopharmaceutical Ligands

Sanda Nastasia Moldovean  1   2 , Diana-Gabriela Timaru  1 , Vasile Chiş  1   2
Affiliations

All-Atom Molecular Dynamics Investigations on the Interactions between D2 Subunit Dopamine Receptors and Three 11C-Labeled Radiopharmaceutical Ligands

Sanda Nastasia Moldovean et al. Int J Mol Sci. .

Abstract

The D2 subunit dopamine receptor represents a key factor in modulating dopamine release. Moreover, the investigated radiopharmaceutical ligands used in positron emission tomography imaging techniques are known to bind D2 receptors, allowing for dopaminergic pathways quantification in the living human brain. Thus, the biophysical characterization of these radioligands is expected to provide additional insights into the interaction mechanisms between the vehicle molecules and their targets. Using molecular dynamics simulations and QM calculations, the present study aimed to investigate the potential positions in which the D2 dopamine receptor would most likely interact with the three distinctive synthetic 11C-labeled compounds (raclopride (3,5-dichloro-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2-hydroxy-6-methoxybenzamide)-RACL, FLB457 (5-bromo-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2,3-dimethoxybenzamide)-FLB457 and SCH23390 (R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine)-SCH)), as well as to estimate the binding affinities of the ligand-receptor complexes. A docking study was performed prior to multiple 50 ns molecular dynamics productions for the ligands situated at the top and bottom interacting pockets of the receptor. The most prominent motions for the RACL ligand were described by the high fluctuations of the peripheral aliphatic -CH3 groups and by its C-Cl aromatic ring groups. In good agreement with the experimental data, the D2 dopamine receptor-RACL complex showed the highest interacting patterns for ligands docked at the receptor's top position.

Keywords: D2 subunit; dopamine receptors; interaction energies; ligand binding; molecular docking; molecular dynamics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PCM (water)-B3LYP/6–311 + G (d,p) optimized molecular structures of the investigated ligands (the 11C atoms are illustrated in pink).
Figure 2
Figure 2
D2DR membrane protein structure.
Figure 3
Figure 3
SASA profiles for ligands docked at D2DR’s top (left) and bottom (right) positions.
Figure 4
Figure 4
Radius of gyration profiles for the two sets of ligands.
Figure 5
Figure 5
RMSF plots of D2DR’s docked ligands.
Figure 6
Figure 6
RMSD values for the three ligands docked at the top and bottom parts of D2DR.
Figure 7
Figure 7
Atom-pair distances for the three ligands docked at the top and bottom parts of D2DR.
Figure 8
Figure 8
Average angle plots for each set of ligands.
Figure 9
Figure 9
The most prominent motions extracted from PCA measurements for the three sets of ligands.
Figure 10
Figure 10
Optimized geometries of the investigated complexes at D2DR’s top docked position at the ONIOM (ωB97XD/6–311+G (d,p):ωB97XD/3–21G) level of theory.
See this image and copyright information in PMC

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