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题名: Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis
作者: Niu, YZ; Shi, DF; Li, LL; Guo, JY; Liu, HX; Yao, XJ(姚小军)
收录类别: SCIE ; PUBMED
出版日期: 2017-04-18
刊名: SCIENTIFIC REPORTS
卷号: 7
出版者: NATURE PUBLISHING GROUP
出版地: LONDON
英文摘要: SETD7 is associated with multiple diseases related signaling pathways. (R)-PFI-2 is the first SETD7 inhibitor with nanomolar inhibitory potency. The activity of (R)-PFI-2 is about 500 times over that of (S)-PFI-2. Understanding the mechanism behind this difference will be helpful to discovery and design of more potent SETD7 inhibitors. A computational study combining molecular dynamics simulation, binding free energy calculations, and residue interaction network (RIN) was performed on the (S)-PFI-2/SETD7 and (R)-PFI-2/SETD7 complexes to explore the molecular mechanism behind the different inhibition activity. The results from Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation show (R)-PFI-2 has lower binding free energy. Residues H252, D256, L267, Y335, G336 and H339 are responsible for the binding of SETD7 to the (R)-PFI-2. RIN analysis indicates van der Waals interaction is critical for the binding of (R)-PFI-2. The results from adaptive basing force (ABF) simulation confirm that the free energy barrier of (R)-PFI-2 dissociating from the SETD7 is larger than that of (S)PFI-2. (S)-PFI-2 and (R)-PFI-2 dissociate from the SETD7 binding site along different reaction coordinate and have potential mean of force (PMF) depth. Our simulations results will be useful to understand molecular mechanism of activity difference between PFI-2 enantiomers against SETD7.
作者部门: [Niu, Yuzhen ; Shi, Danfeng ; Li, Lanlan ; Yao, Xiaojun] Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China ; [Niu, Yuzhen ; Shi, Danfeng ; Li, Lanlan ; Yao, Xiaojun] Lanzhou Univ, Dept Chem, Lanzhou 730000, Peoples R China ; [Guo, Jingyun ; Liu, Huanxiang] Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China ; [Yao, Xiaojun] Lanzhou Univ, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China
通讯作者: Yao, XJ (reprint author), Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China. ; Yao, XJ (reprint author), Lanzhou Univ, Dept Chem, Lanzhou 730000, Peoples R China. ; Yao, XJ (reprint author), Lanzhou Univ, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China.
学科分类: Science & Technology - Other Topics
文章类型: Article
所属项目编号: National Natural Science Foundation of China [21475054] ; Fundamental Research Funds for the Central Universities [lzujbky-2014-191]
所属项目名称: 国家自然科学基金项目 ; 中央高校基本科研业务费专项资金
项目资助者: NSFC ; LZU
语种: 英语
DOI: 10.1038/srep46547
ISSN号: 2045-2322
WOS记录号: WOS:000399368200001
PM记录号: 28417976
IR记录号: WOS:000399368200001
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内容类型: 期刊论文
URI标识: http://ir.lzu.edu.cn/handle/262010/190080
Appears in Collections:化学化工学院_期刊论文

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作者单位: 16CHEM

Recommended Citation:
Niu, YZ,Shi, DF,Li, LL,et al. Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis[J]. SCIENTIFIC REPORTS,2017,7.
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