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学科主题: 临床医学
题名:
Binding mechanism of nine N-phenylpiperazine derivatives and alpha(1A)-adrenoceptor using site-directed molecular docking and high performance affinity chromatography
作者: Zhao, X. F.1; Wang, J.1; Liu, G. X.1; Fan, T. P.1,2; Zhang, Y. J.1; Yu, J.1; Wang, S. X.1; Li, Z. J.3; Zhang, Y. Y.3; Zheng, X. H.1
刊名: RSC ADVANCES
发表日期: 2015
DOI: 10.1039/c5ra10812h
卷: 5, 期:70, 页:57050-57057
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
关键词[WOS]: ALPHA(1)-ADRENERGIC RECEPTOR SUBTYPES ; DRUG-PROTEIN INTERACTIONS ; HISTIDINE-TAGGED PROTEIN ; ORIENTED IMMOBILIZATION ; FRONTAL ANALYSIS ; AGONIST BINDING ; DISCOVERY ; ANTAGONISTS ; LIGANDS ; BETA(2)
英文摘要:

N-Phenylpiperazine derivatives are widely used as clinical drugs for fighting diseases related to the cardiovascular system by mediating the signal pathway of alpha(1)-adrenoceptor. The binding mechanism of nine N-phenylpiperazine derivatives to alpha(1A)-adrenoceptor was explored using molecular docking and high performance affinity chromatography. The methodology involved homology modelling of the three dimensional structure of alpha(1A)-adrenoceptor, predication of the binding behaviors using LIBDOCK and investigation of the thermodynamic behaviors of the binding by frontal analysis. Molecular docking results showed that Asp(106), Gln(177), Ser(188), Ser(192) and Phe(193) of the receptor were the main binding sites for the nine N-phenylpiperazine derivatives binding to alpha(1A)-adrenoceptor. The binding was driven by formation of hydrogen bonds and electrostatic forces. The affinity of these derivatives for the receptor depended on the functional groups of an ionizable piperazine, hydrogen bond acceptor and hydrophobic moiety in the ligand structures. Frontal analysis indicated that the association constants of these compounds for the receptor were determined by their structural deviations in the above-mentioned functional groups. Thermodynamic studies presented negative enthalpy and Gibbs free energy changes with a positive entropy change, providing proof that the binding of the derivatives to alpha(1A)-adrenoceptor was mainly driven by electrostatic forces. This result was in line with the binding mechanism predicted by molecular docking. It is possible to explore the binding mechanism of drug candidates specifically binding to alpha(1A)-adrenoceptor using receptor chromatography.

语种: 英语
所属项目编号: 21475103 ; 2015JM2072 ; 2013KCT-24 ; 2013YQ170525 ; 2013YQ17052509
项目资助者: National Natural Science Foundation of China ; Natural Science Foundation of Shaanxi Province ; program for Innovative Research Team of Shaanxi Province ; Ministry of Science and Technology of the People&prime ; s Republic of China
WOS记录号: WOS:000357805100074
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/64138
Appears in Collections:北京大学第三临床医学院_心血管内科_期刊论文

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作者单位: 1.NW Univ Xian, Coll Life Sci, Key Lab Resource Biol & Biotechnol Western China, Minist Educ, Xian 710069, Peoples R China
2.Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England
3.Peking Univ, Inst Vasc Med, Hosp & Key Lab Mol Cardiovasc Sci 3, Minist Educ, Beijing 100083, Peoples R China

Recommended Citation:
Zhao, X. F.,Wang, J.,Liu, G. X.,et al. Binding mechanism of nine N-phenylpiperazine derivatives and alpha(1A)-adrenoceptor using site-directed molecular docking and high performance affinity chromatography[J]. RSC ADVANCES,2015,5(70):57050-57057.
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