Exploration of N-arylpiperazine Binding Sites of D2 Dopaminergic Receptor.
The crystal structures of the D3 dopamine receptor and several other G-protein coupled receptors (GPCRs) were published in recent times. Those 3D structures are used by us and other scientists as a template for the homology modeling and ligand docking analysis of related GPCRs. Our main scientific interest lies in the field of pharmacologically active N-arylpiperazines that exhibit antipsychotic and/or antidepressant properties, and as such are dopaminergic and serotonergic receptor ligands. In this short review article we are presenting synthesis and biological data on the new N-arylpipereazine as well our results on molecular modeling of the interactions of those N-arylpiperazines with the model of D2 dopamine receptors. To obtain that model the crystal structure of the D3 dopamine receptor was used. Our results show that the N-arylpiperazines binding site consists of two pockets: one is the orthosteric binding site where the N-arylpiperazine part of the ligand is docked and the second is a non-canonical accessory binding site for N-arylpipereazine that is formed by a second extracellular loop (ecl2) of the receptor. Until now, the structure of this receptor region was unresolved in crystal structure analyses of the D3 dopamine receptor. To get a more complete picture of the ligand - receptor interaction, DFT quantum mechanical calculations on N-arylpiperazine were performed and the obtained models were used to examine those interactions.
School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire, UK. v.soskic@herts.ac.uk.
Vukic
V
Soskic
Vladimir
V
Sukalovic
Sladjana
S
Kostic-Rajacic
D001665:Binding Sites; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism*
D010879:Piperazines; D017448:Receptors, Dopamine D2