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Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase
Wang, Zhiguo2,3; Ling, Baoping1; Zhang, Rui2,3; Suo, Yourui2; Liu, Yongjun1,2; Yu, Zhangyu1; Liu, Chengbu1
2009-09-01
发表期刊JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷号28期号:2页码:162-169
文章类型Article
摘要Phenolic marine natural product is a kind of new potential aldose reductase inhibitors (ARIs). In order to investigate the binding mode and inhibition mechanism, molecular docking and dynamics studies were performed to explore the interactions of six phenolic inhibitors with human aldose reductase (hALR2). Considering physiological environment, all the neutral and other two ionized states of each phenolic inhibitor were adopted in the simulation. The calculations indicate that all the inhibitors are able to form stable hydrogen bonds with the hALR2 active pocket which is mainly constructed by residues TYR48, HIS110 and TRP111, and they impose the inhibition effect by occupying the active space. In all inhibitors, only La and its two ionized derivatives La_ion1 and La_ion2, in which neither of the ortho-hydrogens of 3-hydroxyl is substituted by Br, bind with hALR2 active residues using the terminal 3-hydroxyl. While, all the other inhibitors, at least one of whose ortho-sites of 3- and 6-hydroxyls are substituted by Br substituent which take much electron-withdrawing effect and steric hindrance, bind with hALR2 through the lactone group. This means that the Br substituent can effectively regulate the binding modes of phenolic inhibitors. Although the lactone bound inhibitors have relatively high RMSD values, our dynamics study shows that both binding modes are of high stability. For each inhibitor molecule, the ionization does not change its original binding mode, but it does gradually increase the binding free energy, which reveals that besides hydrogen bonds, the electrostatic effect is also important to the inhibitor–hALR2 interaction.; Phenolic marine natural product is a kind of new potential aldose reductase inhibitors (ARIs). In order to investigate the binding mode and inhibition mechanism, molecular docking and dynamics studies were performed to explore the interactions of six phenolic inhibitors with human aldose reductase (hALR2). Considering physiological environment, all the neutral and other two ionized states of each phenolic inhibitor were adopted in the simulation. The calculations indicate that all the inhibitors are able to form stable hydrogen bonds with the hALR2 active pocket which is mainly constructed by residues TYR48, HIS110 and TRP111, and they impose the inhibition effect by occupying the active space. In all inhibitors, only La and its two ionized derivatives La_ion1 and La_ion2, in which neither of the ortho-hydrogens of 3-hydroxyl is substituted by Br, bind with hALR2 active residues using the terminal 3-hydroxyl. While, all the other inhibitors, at least one of whose ortho-sites of 3- and 6-hydroxyls are substituted by Br substituent which take much electron-withdrawing effect and steric hindrance, bind with hALR2 through the lactone group. This means that the Br substituent can effectively regulate the binding modes of phenolic inhibitors. Although the lactone bound inhibitors have relatively high RMSD values, our dynamics study shows that both binding modes are of high stability. For each inhibitor molecule, the ionization does not change its original binding mode, but it does gradually increase the binding free energy, which reveals that besides hydrogen bonds, the electrostatic effect is also important to the inhibitor-hALR2 interaction. (C) 2009 Elsevier Inc. All rights reserved.
关键词Phenolic Aris Aldose Reductase Molecular Docking Dynamics Inhibition
WOS标题词Science & Technology ; Life Sciences & Biomedicine ; Technology ; Physical Sciences
学科领域生物科学
关键词[WOS]DIABETIC COMPLICATIONS ; CATALYTIC MECHANISM ; MUTANT ENZYME ; SITE ; SIMULATIONS ; TYROSINE-48 ; DERIVATIVES ; SELECTIVITY
收录类别SCI
语种英语
WOS研究方向Biochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology
WOS类目Biochemical Research Methods ; Biochemistry & Molecular Biology ; Computer Science, Interdisciplinary Applications ; Crystallography ; Mathematical & Computational Biology
WOS记录号WOS:000271349100009
引用统计
文献类型期刊论文
条目标识符http://210.75.249.4/handle/363003/1446
专题中国科学院西北高原生物研究所
作者单位1.Shandong Univ, Sch Chem & Chem Engn, Jinan 250100, Shandong, Peoples R China
2.Chinese Acad Sci, NW Inst Plateau Biol, Xining 810001, Qinghai, Peoples R China
3.Chinese Acad Sci, Grad Univ, Beijing 10049, Peoples R China
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GB/T 7714
Wang, Zhiguo,Ling, Baoping,Zhang, Rui,et al. Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2009,28(2):162-169.
APA Wang, Zhiguo.,Ling, Baoping.,Zhang, Rui.,Suo, Yourui.,Liu, Yongjun.,...&Liu, Chengbu.(2009).Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase.JOURNAL OF MOLECULAR GRAPHICS & MODELLING,28(2),162-169.
MLA Wang, Zhiguo,et al."Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase".JOURNAL OF MOLECULAR GRAPHICS & MODELLING 28.2(2009):162-169.
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