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

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.

Identification of Some Glutamic Acid Derivatives with Biological Potential by Computational Methods

“…The main residues in the D subunit of the GS enzyme involved in interactions (within 1.49–2.81 Å) with the 4Db6 ligand are THR-223 (2 bonds) and GLU-129. Hydrogen bond connections play a key role in determining protein–ligand interactions [ 160 , 165 ]. In addition, the first conformation shows four active torsions: between C4 and P8, CA6 and C7, P8 and C9, and P8 and O11 [ 160 ].…”

Exploring Geometrical, Electronic and Spectroscopic Properties of 2-Nitroimidazole-Based Radiopharmaceuticals via Computational Chemistry Methods

“…Thus, we consider that our results related to the structure and conformations of the investigated compounds could be useful for docking studies and ligand-receptor interactions [8,9]. The predicted spectroscopic properties might also be of help for drug monitoring [10], for drug detection or for pharmaceutical research and development [11].…”