Tetrahydroisoquinolines acting as dopaminergic ligands. A molecular modeling study using MD simulations and QM calculations

Abstract

A molecular modeling study on 16 1-benzyl tetrahydroisoquinolines (BTHIQs) acting as dopaminergic ligands was carried out. By combining molecular dynamics simulations with ab initio and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of BTHIQs interacting with the human dopamine D2 receptor (D2 DR) is reported here, providing a clear picture of the binding interactions of BTHIQs from both structural and energetic viewpoints. Molecular aspects of the binding interactions between BTHIQs and the D2 DR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental pKi values was obtained, predicting the potential dopaminergic effect of non-synthesized BTHIQs.

2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

“…In general, the three compounds displayed their pharmacophoric portions in a closely related spatial form to that reported for dopamine [17,18]. Consistent with previous experimental [36] and theoretical [37] data, the simulation indicated the relevance of the negatively charged aspartate 114 (D114) for ligand binding.…”

“…We observed that the presence of hydroxyls groups in this ring caused increased affinity for the D 1 -like and D 2 -like DR families, while blockade of these hydroxyls groups resulted in decreased affinity [8,[12][13][14][15]. Moreover, the presence of a halogen in the A-ring led to a selective binding at least to one of the two DR subtypes investigated [8,16,17]. Therefore, we have prepared three series of THPBs: 2,11-dihydroxy-3-chloro-THPB (series 1), 2,3-dihydroxy-11-methoxy-THPB (series 2) and 2,3,11-trihydroxy-THPB and 2,3,9-trihydroxy-THPB (series 3) and differently substituted analogues (Figure 1).…”

“…The higher affinity for D 1 and D 2 DR of compounds with free phenolic group than those without was previously described albeit in several isoquinolines [8,12,16,21]. b) In previous studies in which dopaminergic affinity of BTHIQs was evaluated, the presence of a chlorine atom into the A-ring (ortho of oxygenated group) resulted in increased affinity and selectivity towards D 2 DR [8,[16][17][18]. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D 1 DR but dramatically reduced the selectivity for D 2 DR (see 3b vs 9c in Tabla 1).…”

“…In order to determine the residues of the D 2 DR active site involved in the interactions, the residues proposed by Andujar et al [17] and Soriano-Ursua et al were first identified. Then MM-GBSA free energy decomposition using the mm_pbsa program in AMBER12 was employed to corroborate the amino acids interacting with the ligands.…”

“…Previous studies from our group have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) have affinity for DR in striate membranes of rat brain tissue which was likely due to their structural similarities to dopamine [8][9][10][11][12][13][14][15][16][17][18].…”