Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Abstract

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q2 = 0.603, R2ncv = 0.829, R2pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q2 = 0.506, R2ncv =0.838, R2pre = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R1 substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists

“…Using bovine Rhodopsin crystal structures 1F88 and 1GZM, which is also a transmembrane protein, to build TM structure of GPCRs (G protein-coupled receptor) like mGluR1 and mGluR5, is applied recently [ 20 – 22 ]. Thus we attempted to build mGluR2 homology model based on 1F88 and 1GZM.…”

Current drug treatments targeting dopamine D3 receptor

“…quantitative SAR based on prediction of 3D interaction of the ligand in the pocket of the modeled receptor), where D3R is modeled on other G protein-coupled receptors, mainly the β 2 adrenergic receptor (Boeckler et al, 2005a;Carlsson et al, 2011;Liu et al, 2011;Lopez et al, 2010;Varady et al, 2003;Wang et al, 2010). The latter two approaches are often complementary to classical SAR studies.…”

Beyond Small-Molecule SAR

“…Small molecule comparative molecular field analysis (CoMFA) or comparative molecular similarities index analysis (CoMSIA) and 3D-QSAR studies have been employed in the past (Boeckler et al, 2005; Liu et al, 2011; Lopez et al, 2010; Salama et al, 2007; Wang et al, 2010), however the advent of GPCR homology modeling has opened additional platforms from which to design molecules with theoretically optimized interactions in the targeted receptor binding pocket(s) at the molecular level. As the high-resolution crystal structure of the D3 receptor was recently solved with the D2/D3 antagonist/inverse agonist eticlopride (Chien et al, 2010), a new opportunity for structure-based drug design is available and is being used for the design of novel compounds.…”