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题名: Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists using 3D-QSAR and molecular docking
作者: Yan, Yulian1;  Li, Yan1;  Zhang, Shuwei1;  Ai, Chunzhi2
关键词: 3D-QSAR ;  Integrin alpha(v)beta(3) ;  Integrin alpha(IIb)beta(3) ;  Antagonist ;  CoMFA ;  CoMSIA
刊名: JOURNAL OF MOLECULAR GRAPHICS & MODELLING
发表日期: 2011-02-01
DOI: 10.1016/j.jmgm.2010.12.008
卷: 29, 期:5, 页:747-762
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Technology ;  Physical Sciences
类目[WOS]: Biochemical Research Methods ;  Biochemistry & Molecular Biology ;  Computer Science, Interdisciplinary Applications ;  Crystallography ;  Mathematical & Computational Biology
研究领域[WOS]: Biochemistry & Molecular Biology ;  Computer Science ;  Crystallography ;  Mathematical & Computational Biology
英文摘要: The development of injectable integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists attracts much attention of research for treating of acute ischemic diseases in recent years. In this work, based on a dataset composed of 102 tricyclic piperazine/piperidine furnished dual alpha(v)beta(3) and alpha(IIb)beta(3) antagonists, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), and molecular docking were applied to reveal the requisite 3D structural features impacting the biological activities. Our statistical results show that the ligand-based 3D-QSAR models for both the alpha(v)beta(3) and alpha(IIb)beta(3) studies exhibited satisfactory internal and external predictability, i.e., for the CoMFA models, results of Q(2) = 0.48, R-ncv(2) = 0.87, R-pred(2) = 0.71 for alpha(v)beta(3) and Q(2) = 0.50, R-ncv(2) = 0.85, R-pred(2) = 0.72 for alpha(IIb)beta(3) analysis were obtained, and for the CoMSIA ones, the outcomes of Q(2) = 0.55, R-ncv(2) = 0.90, R-pred(2) = 0.72 for alpha(v)beta(3) and Q(2) = 0.52, R-ncv(2) = 0.88, R-pred(2) = 0.74 for alpha(IIb)beta(3) were achieved respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that that the most crucial interactions occurring between the tricyclic piperazine/piperidine derivatives and alpha(v)beta(3)/alpha(IIb)beta(3) receptor ligand binding pocket are H-bonding, and the key amino acids impacting the interactions are Arg214, Asn215, Ser123, and Lys253 for alpha(v)beta(3), but Arg214, Asn215, Ser123 and Tyr190 for alpha(IIb)beta(3) receptors, respectively. Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the alpha(v)beta(3)/alpha(IIb)beta(3) antagonistic activity. The potencies for antagonists to inhibit isolated alpha(v)beta(3) and alpha(IIb)beta(3) are linear correlated, indicating that similar interaction mechanisms may exist for the series of molecules. To our best knowledge this is the first report on 3D-QSAR modeling of these dual alpha(v)beta(3)/alpha(IIb)beta(3) antagonists. The results obtained should provide information for better understanding of the mechanism of antagonism and thus be helpful in design of novel potent dual alpha(v)beta(3)/alpha(IIb)beta(3) antagonists. (C) 2011 Elsevier Inc. All rights reserved.
关键词[WOS]: PHARMACOPHORE-BASED MOLECULES ;  GLYCOPROTEIN-IIB-IIIA ;  ALPHA(V)BETA(3) INTEGRIN ;  INTEGRIN-ALPHA(V)BETA(3) ANTAGONISTS ;  VITRONECTIN RECEPTOR ;  POTENT ANTAGONISTS ;  GLANZMANN THROMBASTHENIA ;  BINDING-AFFINITY ;  BETA 3 ;  FIBRINOGEN
语种: 英语
WOS记录号: WOS:000288236400018
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142663
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.Chinese Acad Sci, Dalian Inst Chem Phys, Grad Sch, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Yan, Yulian,Li, Yan,Zhang, Shuwei,et al. Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists using 3D-QSAR and molecular docking[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2011,29(5):747-762.
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