Molecular recognition and binding mechanism of N-alkyl- benzyltetrahydroisoquinolines to the D1 dopamine receptor. A computational approach

Abstract

In order to better understand, at sub-molecular level, the minimal structural requirements for the recognition process in the inhibitory activity, a series of N-alkyl-benzyltethrahydroisoquinolines (BTHIQs) were examined as Dopamine D1 receptor antagonist variants. According to the cardinal role of the electrostatic factors during this interaction, ab initio and density functional theory (DFT) calculations were performed for a better understanding of the recognition process at the sub-molecular level. RHF/3-21G, RHF/6-31G(d) and B3LYP/6-31G++(d,p) in the gas phase, plus DFT calculations using the IPCM solvation model were carried out for all the complexes. We simulate the electronic interactions between BTHIQs with its biological receptor in terms of smaller molecules. H3C-COOH was used to mimic the side chain of Aspartic acid and CH3OH mimicked the side chain of Serine; alternative moieties present on the BTHIQ derivatives were used as the different partenaires. Using the above mentioned computational model, we are able to interpret the basic behaviours and predict some additional features of BTHIQ-Dopamine D1 receptor interaction.