Modeling key interactions between the second extracellular loop of the dopamine D2 receptor and arylpiperazine ligands

Abstract: Second extracellular loop (ecl2) of the dopamine (DA) D2 receptor is an essential part of the binding pocket of dopaminergic ligands. To form a part of the ligand-binding surface, it has to fold down into the transmembrane domain of the DA receptor. The current study describes the modeling of the D2 DA receptor ecl2 and its interactions with arylpiperazine ligands. In order to model the D2 DA receptor ecl2, several arylpiperazine ligands were used to propose a pharmacophore model. D2 DA receptor ecl2 model was built using Accelrys Discovery Studio. To test the proposed model, docking analysis was performed and key amino acid residues were determined. The proposed receptor–ligand interactions were rationalized and compared with measured binding affinities. It is shown that D2 DA receptor ecl2 significantly participates in the formation of the receptor–ligand complex through aromatic, hydrophobic and polar interaction. Considering them would benefit molecular modeling of Gprotein-coupled receptors (GPCRs) and facilitate the design of novel active compounds.