The influence of dispersive interactions on the binding affinities of ligands with an arylpiperazine moiety to the dopamine D2 receptor

Abstract

Several isosteric 1,3-dihydro-5-[2-(4-aryl-1-piperazinyl)ethyl]-2H-benzimidazole-2-thiones were used to investigate the interactions of different ligands with the binding site of the D2 receptor. Due to limitations of the simulation methods, docking analysis failed to show precisely the interactions that influence the binding affinity of the ligands. It is presumed that dispersive forces or more precisely edge-to-face interactions play an important role in the binding process, especially for the lipophilic part of the ligands. In order to confirm this hypothesis, ab initio calculations were applied on a model system in order to find the stabilization energies of potential edge-to-face interactions and then to correlate them with the ligand affinity. The obtained results indicate that there is a significant correlation between the strength of dispersive inter-actions and ligand affinity. It was shown that for the calculation of stabilization energies of modeled receptor–ligand complexes the Becke “half-and-half” hybrid DFT method can be used, thus speeding up the usually long calculation time and reducing the required computer strength