兰州大学机构库 >化学化工学院
Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis
Niu, YZ; Shi, DF; Li, LL; Guo, JY; Liu, HX; Yao, XJ(姚小军); 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.
收录类别SCIE ; PUBMED
2017-04-18
发表期刊SCIENTIFIC REPORTS
卷号7
出版者NATURE PUBLISHING GROUP
出版地LONDON
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...更多
学科领域Science & Technology - Other Topics
所属项目编号National Natural Science Foundation of China [21475054] ; Fundamental Research Funds for the Central Universities [lzujbky-2014-191]
资助项目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
DOI10.1038/srep46547
ISSN2045-2322
文章类型Article
语种英语
WOS记录号WOS:000399368200001
PM记录号28417976
IR记录号WOS:000399368200001
第一机构
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文献类型期刊论文
条目标识符http://ir.lzu.edu.cn/handle/262010/190080
Collection化学化工学院
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.
作者单位16CHEM
Recommended Citation:
GB/T 7714
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.
APA Niu, YZ.,Shi, DF.,Li, LL.,Guo, JY.,Liu, HX.,...&Yao, XJ .(2017).Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis.SCIENTIFIC REPORTS,7.
MLA Niu, YZ,et al."Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis".SCIENTIFIC REPORTS 7(2017).
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