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学科主题: 物理化学
题名: Insight into the binding mode and the structural features of the pyrimidine derivatives as human A(2A) adenosine receptor antagonists
作者: Zhang, Lihui1;  Liu, Tianjun2;  Wang, Xia1;  Wang, Jinan1;  Li, Guohui3;  Li, Yan4;  Yang, Ling5;  Wang, Yonghua1
通讯作者: YonghuaWang
关键词: Pyrimidine derivatives ;  Human A(2A) adenosine receptor ;  Molecular docking ;  Molecular dynamics ;  Thermodynamic analysis ;  3D-QSAR
刊名: BIOSYSTEMS
发表日期: 2014
DOI: 10.1016/j.biosystems.2013.04.003
卷: 115, 期:1, 页:13-22
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biology ;  Mathematical & Computational Biology
研究领域[WOS]: Life Sciences & Biomedicine - Other Topics ;  Mathematical & Computational Biology
英文摘要: The interaction of 278 monocyclic and bicyclic pyrimidine derivatives with human A(2A) adenosine receptor (AR) was investigated by employing molecular dynamics, thermodynamic analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches. The binding analysis reveals that the pyrimidine derivatives are anchored in TM2, 3, 5, 6 and 7 of A(2A) AR by the aromatic stacking and hydrogen bonding interactions. The key residues involving Phe168, Glu169, and Asn253 stabilize the monocyclic and bicyclic cores of inhibitors. The thermodynamic analysis by molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) approach also confirms the reasonableness of the binding modes. In addition, the ligand-/receptor-based comparative molecular similarity indices analysis (CoMSIA) models of high statistical significance were generated and the resulting contour maps correlate well with the structural features of the antagonists essential for high A(2A) AR affinity. A minor/bulky group with negative charge at C2/C6 of pyrimidine ring respectively enhances the activity for all these pyrimidine derivatives. Particularly, the higher electron density of the ring in the bicyclic derivatives, the more potent the antagonists. The obatined results might be helpful in rational design of novel candidate of A(2A) adenosine receptor antagonist for treatment of Parkinson's disease. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
关键词[WOS]: PROTEIN-COUPLED RECEPTORS ;  PARKINSONS-DISEASE ;  MOLECULAR-DYNAMICS ;  AUTOMATED DOCKING ;  R(M)(2) METRICS ;  FORCE-FIELD ;  QSPR MODELS ;  DRUG DESIGN ;  VALIDATION ;  DISCOVERY
语种: 英语
WOS记录号: WOS:000330500100003
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/144015
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.Northwest A&F Univ, Bioinformat Ctr, Yangling 712100, Shaanxi, Peoples R China
2.Northwest A&F Univ, Coll Econ & Management, Yangling 712100, Shaanxi, Peoples R China
3.Chinese Acad Sci, Lab Mol Modeling & Design, Dalian 116024, Liaoning, Peoples R China
4.Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Liaoning, Peoples R China
5.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Zhang, Lihui,Liu, Tianjun,Wang, Xia,et al. Insight into the binding mode and the structural features of the pyrimidine derivatives as human A(2A) adenosine receptor antagonists[J]. BIOSYSTEMS,2014,115(1):13-22.
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