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Int. J. Mol. Sci. 2011, 12(2), 1196-1221; doi:10.3390/ijms12021196

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

1,* , 1
1 School of Chemical Engineering, Dalian University of Technology, Dalian, 116012, Liaoning, China 2 Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, 712100, China 3 Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian, 116023, Liaoning, China
* Author to whom correspondence should be addressed.
Received: 30 December 2010 / Revised: 25 January 2011 / Accepted: 9 February 2011 / Published: 18 February 2011
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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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.
Keywords: 3D-QSAR; dopamine D3 receptor; antagonist; CoMFA; CoMSIA 3D-QSAR; dopamine D3 receptor; antagonist; CoMFA; CoMSIA
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Liu, J.; Li, Y.; Zhang, S.; Xiao, Z.; Ai, C. Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics. Int. J. Mol. Sci. 2011, 12, 1196-1221.

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