Exploration of N-arylpiperazine Binding Sites of D2 Dopaminergic Receptor

• Published in: Mini reviews in medicinal chemistry Vol. 15; no. 12; p. 988
• Main Authors: Soskic, Vukic, Sukalovic, Vladimir, Kostic-Rajacic, Sladjana
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2015
• Subjects: Binding Sites; Humans; Molecular Structure; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Quantum Theory; Receptors, Dopamine D2 - chemistry; Receptors, Dopamine D2 - metabolism
• ISSN: 1875-5607
• DOI: 10.2174/138955751512150731112448

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.