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Binding mechanism of nine N-phenylpiperazine derivatives and alpha(1A)-adrenoceptor using site-directed molecular docking and high performance affinity chromatography
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
2015
DOI10.1039/c5ra10812h
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
WOS记录号WOS:000357805100074
项目编号21475103 ; 2015JM2072 ; 2013KCT-24 ; 2013YQ170525 ; 2013YQ17052509
资助机构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
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/64138
专题北京大学第三临床医学院_心血管内科
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
推荐引用方式
GB/T 7714
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.
APA Zhao, X. F..,Wang, J..,Liu, G. X..,Fan, T. P..,Zhang, Y. J..,...&Zheng, X. H..(2015).Binding mechanism of nine N-phenylpiperazine derivatives and alpha(1A)-adrenoceptor using site-directed molecular docking and high performance affinity chromatography.RSC ADVANCES,5(70),57050-57057.
MLA Zhao, X. F.,et al."Binding mechanism of nine N-phenylpiperazine derivatives and alpha(1A)-adrenoceptor using site-directed molecular docking and high performance affinity chromatography".RSC ADVANCES 5.70(2015):57050-57057.
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