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题名: Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists
作者: Zhang, Meng-Qi1;  Zhang, Xiao-Le2;  Li, Yan1;  Fan, Wen-Jia1;  Wang, Yong-Hua3, 4;  Hao, Ming1;  Zhang, Shu-Wei1;  Ai, Chun-Zhi3
关键词: 3D-QSAR ;  mGluR2 antagonist ;  CoMFA ;  CoMSIA ;  pharmacophore modeling
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2011-09-01
DOI: 10.3390/ijms12095999
卷: 12, 期:9, 页:5999-6023
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: MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[b][1,4] diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [H-3]-LY354740; activity II: mGluR2 (1S, 3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R-ncv(2) of 0.868, R-pred(2) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R-ncv(2) = 0.899, R-pred(2) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R-ncv(2) = 0.715, R-pred(2) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R-7, R-3 and position A benefit activity I of the antagonists, but decrease it when projected in R-8 and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists.
关键词[WOS]: METABOTROPIC GLUTAMATE RECEPTORS ;  MOLECULAR-DYNAMICS ;  BIOLOGICAL-ACTIVITY ;  COMBINED 3D-QSAR ;  BINDING ;  INHIBITORS ;  DOCKING ;  AGONIST ;  DERIVATIVES ;  LY354740
语种: 英语
WOS记录号: WOS:000295213600040
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142656
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, Dept Mat Sci & Chem Engn, Dalian 116024, Liaoning, Peoples R China
2.Dalian Univ Technol, Dept Math Sci, Dalian 116024, Liaoning, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Grad Sch, Dalian 116023, Liaoning, Peoples R China
4.NW A&F Univ, Ctr Bioinformat, Yangling 712100, Shaanxi, Peoples R China

Recommended Citation:
Zhang, Meng-Qi,Zhang, Xiao-Le,Li, Yan,et al. Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2011,12(9):5999-6023.
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