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

International Journal of Molecular Sciences

Jing Liu²  Yan Li²  Shuwei Zhang²  Zhengtao Xiao¹ 

[1] Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, 712100, China; E-Mail:;School of Chemical Engineering, Dalian University of Technology, Dalian, 116012, Liaoning, China; E-Mails:

关键词: 3D-QSAR;    dopamine D3 receptor;    antagonist;    CoMFA;    CoMSIA;   

DOI  :  10.3390/ijms12021196

来源: mdpi

【 摘 要 】

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, R²_ncv = 0.829, R²_pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q² = 0.506, R²_ncv =0.838, R²_pre = 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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.