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ACS Chem Neurosci. 2017 Apr 19;8(4):826-836. doi: 10.1021/acschemneuro.6b00396. Epub 2017 Jan 20.

Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor.

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Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University , Istanbul, Turkey.
Departments of Pharmacology and Psychiatry, University of Toronto , 260 Heath Street West, Unit 605, M5P 3L6 Toronto, Ontario Canada.
Max-Planck Institute for Dynamics of Complex Technical Systems, Molecular Simulations and Design Group, Sandtorstrasse 1, 39106 Magdeburg, Germany.
Department of Chemistry, Istanbul Technical University , 34467 Istanbul, Turkey.


The dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [3H](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO) revealed Ki values of 32 nM for the D2highR and 52 μM for the D2lowR. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2highR were -9.46 and -8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2highR is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2highR conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R.


ACR16; Antipsychotics; MM/PBSA; dopamine D2 receptor; molecular docking; molecular dynamics simulations; molecular modeling; schizophrenia

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