Understanding the structural requirements of hybrid (S)-6-((2-(4-phenylpiperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol and its analogs as D2/D3 receptor ligands: a 3D QSAR investigation

Abstract

To gain insights into the structural requirements for dopamine D2 and D3 agonists in the treatment of Parkinson's disease (PD) and to elucidate the basis of selectivity for D3 over D2 (D2/D3), 3D quantitative structure–activity relationship (3D QSAR) investigations using CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) methods were performed on a series of 45 structurally related D2 and D3 dopaminergic ligands. Two alignment methods (atom-based and flexible) and two charge calculation methods (Gasteiger–Hückel and AM1) were used in the present study. Overall, D2 affinity and selectivity (D2/D3) models performed better with r_cv² values of 0.71 and 0.63 for CoMFA and 0.71 and 0.79 for CoMSIA, respectively. The corresponding predictive r² values for the CoMFA and CoMSIA models were 0.92 and 0.86 and 0.91 and 0.78, respectively. The CoMFA models generated using the flexible alignment outperformed the models with the atom-based alignment in terms of relevant statistics and interpretability of the generated contour maps while CoMSIA models obtained using atom-based alignment showed superiority in terms of internal and external predictive abilities. The presence of the carbonyl group (CO) attached to the piperazine ring and the hydrophobic biphenyl ring were found to be the most important features responsible for the D3 selectivity over D2. This study can be further utilized to design and develop selective and potent dopamine agonists to treat PD.