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 interactions 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.

Nekoliko izosternih 1,3-dihidro-5-[2-(4-aril-1-piperazinil)etil]-2H-benzimidazol-2-tiona je korišćeno da bi se ispitale interakcije različitih liganada sa vezivnim mestom dopaminskog D2 receptora. Zbog ograničenja metoda korišćenih za simulaciju vezivanja, analiza ovih rezultata nije mogla da pokaže preciznije koje interakcije utiču na afinitet vezivanja liganada. Pretpostavljeno je da disperzivne sile, ili preciznije, tzv. edge-to-face interakcije, igraju značajnu ulogu u procesu vezivanja, naročito u lipofilnom delu liganda. Da bi se potvrdila ova hipoteza primenom ab initio izračunavanja na model sistem, pokušano je izračunavanje stabilizacione energije ovih interakcija i njeno dovođenje u vezu sa afinitetom liganada. Dobijeni rezultati ukazuju da postoji značajna korelacija između jačine disperzivnih interakcija i afiniteta liganda. Pokazano je da se pri izračunavanju stabilizacionih energija modelovanih kompleksa ligand-receptor može upotrebiti Beckeova 'half-and-half' hibridna DFT metoda, što značajno smanjuje vreme potrebno za izračunavanja i potrebne računarske resurse.