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题名: Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics
作者: Liu, Jing1;  Li, Yan1;  Zhang, Shuwei1;  Xiao, Zhengtao2;  Ai, Chunzhi3
关键词: 3D-QSAR ;  dopamine D3 receptor ;  antagonist ;  CoMFA ;  CoMSIA
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2011-02-01
DOI: 10.3390/ijms12021196
卷: 12, 期:2, 页:1196-1221
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: 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 (Q(2) = 0.603, R-ncv(2) = 0.829, R-pre(2) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R-ncv(2) = 0.838, R-pre(2) = 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 R-3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R-1 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.
关键词[WOS]: D-3 RECEPTOR ;  3-DIMENSIONAL STRUCTURE ;  BIOLOGICAL EVALUATION ;  DRUG DISCOVERY ;  HIGH-AFFINITY ;  FORCE-FIELD ;  COMFA ;  INHIBITORS ;  COMSIA ;  LIGANDS
语种: 英语
WOS记录号: WOS:000287732000023
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142669
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Liaoning, Peoples R China
2.NW A&F Univ, Ctr Bioinformat, Yangling 712100, Shaanxi, Peoples R China
3.Chinese Acad Sci, Grad Sch, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Liu, Jing,Li, Yan,Zhang, Shuwei,et al. Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2011,12(2):1196-1221.
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