基于分子对接技术筛选中药来源的HDAC3/8小分子抑制剂

赵诗雨; 刘玉甜; 杨炳友; 刘艳; 吕邵娃

doi:10.13422/j.cnki.syfjx.20192446

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基于分子对接技术筛选中药来源的HDAC3/8小分子抑制剂

数据挖掘 | 更新时间：2021-02-09

- 基于分子对接技术筛选中药来源的HDAC3/8小分子抑制剂
- Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking
- 中国实验方剂学杂志 2020年26卷第7期页码：186-194
- 作者机构：
  
  黑龙江中医药大学　省部共建教育部北药基础与应用研究重点实验室，黑龙江省中药及天然药物药效物质基础研究重点实验室，哈尔滨　 150000
- 作者简介：
  
  [第一作者]　赵诗雨，在读硕士，从事中药新药的研究与开发，Tel：0451-87266916，E-mail：1921004800@qq.com
  *吕邵娃，教授，硕士生导师，从事新药研究与开发工作，Tel：0451-87266916，E-mail：lswa5599@hotmail.com
- 基金信息：
  
  黑龙江中医药大学科研基金项目(2018xy04);国家自然科学基金项目(81373929)
- DOI：10.13422/j.cnki.syfjx.20192446
  中图分类号： R22; R24; R28; C37; Q512
- 收稿日期：2019-07-04，
  
  网络出版日期：2019-08-27，
  
  纸质出版日期：2020-04-05
- 稿件说明：
移动端阅览
赵诗雨, 刘玉甜, 杨炳友, 等. 基于分子对接技术筛选中药来源的HDAC3/8小分子抑制剂[J]. 中国实验方剂学杂志, 2020,26(7):186-194.

Shi-yu ZHAO, Yu-tian LIU, Bing-you YANG, et al. Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(7): 186-194.
赵诗雨, 刘玉甜, 杨炳友, 等. 基于分子对接技术筛选中药来源的HDAC3/8小分子抑制剂[J]. 中国实验方剂学杂志, 2020,26(7):186-194. DOI： 10.13422/j.cnki.syfjx.20192446.

Shi-yu ZHAO, Yu-tian LIU, Bing-you YANG, et al. Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(7): 186-194. DOI： 10.13422/j.cnki.syfjx.20192446.

摘要

目的：

发现具有组蛋白去乙酰化酶(HDAC)3/8抑制活性的中药小分子活性成分。

方法：

应用AutoDock 4.2.6软件进行分子对接技术，以HDAC抑制剂曲古抑菌素A(TSA)为参照，对19种中药小分子成分进行筛选，设定默认对接构象数，获得对接结合能、活性位点氨基酸残基和氢键，并进行生物活性验证。

结果：

19种中药小分子与HDAC3和HDAC8均有不同程度的结合能，其中熊果酸、防己诺林碱和粉防己碱对HDAC3和HDAC8的结合能较低，结合活性较强。防己诺林碱与HDAC3处在1位点的最优结合能最低(-26.71 kJ·mol

-1

)，与HDAC8处在9位点的最优结合能最低(-26.84 kJ·mol

-1

)；粉防己碱与HDAC3处在13位点的最优结合能最低(-26.38 kJ·mol

-1

)，与HDAC8处在12位点的结合能最低(-25.41 kJ·mol

-1

)；熊果酸与HDAC3处在16位点的结合能最低(-25.83 kJ·mol

-1

)，与HDAC8处在8位点的最优结合能最低(-35.62 kJ·mol

-1

)。通过PyMOL 2.3.1渲染出了3种小分子对接位点氨基酸，熊果酸与HDAC3/8结合时，活性位点均产生2个氢键，且相互作用较强，同时有较多活性位点氨基酸相连接。防己诺林碱与HDAC3活性位点产生2个氢键，与HDAC8活性位点产生1个氢键，与部分活性位点氨基酸进行疏水性结合。粉防己碱与HDAC3/8均无氢键作用，对接位点均由4种活性氨基酸对接。对接效果最优的3种小分子(熊果酸、防己诺林碱和粉防己碱)在500 μmol·L

-1

和100 μmol·L

-1

浓度下对HDAC3/8均有抑制活性，且抑制活性在选出的10种小分子中仍最优。

结论：

在被筛选的19个小分子中，熊果酸、粉防己碱和防己诺林碱有可能是新型HDAC3/8抑制靶点抗炎药物，可为探索新的抗炎药物提供参考。

Abstract

Objective:

To discover a small molecule active ingredient of traditional Chinese medicine (TCM) with the inhibitory activity of histone deacetylase (HDAC) 3/8.

Method:

The molecular docking technique was performed by AutoDock 4.2.6 software. Trichostatin A (TSA) was used as a reference to screen 19 small molecular components from TCM

and the default docking conformation number was set to obtain the docking binding energy

active site amino acid residues and hydrogen bonds

and the biological activity was verified.

Result:

The binding energies of 19 small molecule components from TCM to HDAC3 and HDAC8 were different. Among them

ursolic acid

fangchinoline and tetrandrine have low binding energies to HDAC3 and HDAC8

and their binding activities were strong. The optimal binding energy of fangchinoline and HDAC3 at the site 1 was the lowest (-26.71 kJ·mol

-1

)

and that of HDAC8 at the site 9 was the lowest (-26.84 kJ·mol

-1

). The optimal binding energy of tetrandrine and HDAC3 at the site 13 was the lowest (-26.38 kJ·mol

-1

)

and that of HDAC8 at the site 12 was the lowest (-25.41 kJ·mol

-1

). In addition

the binding energy of ursolic acid and HDAC3 at the site 16 was the lowest (-25.83 kJ·mol

-1

)

and that of HDAC8 at the site 8 was the lowest (-35.62 kJ·mol

-1

). Three kinds of amino acids at the docking site of small molecules were rendered by PyMOL 2.3.1.When ursolic acid was combined with HDAC3/8

the active sites produced two hydrogen bonds

and the interaction was strong

and many amino acids were connected at the active site. The fangchinoline formed two hydrogen bonds with the active site of HDAC3 and one hydrogen bond with the active site of HDAC8

and hydrophobic binding with some active site amino acids. There was no hydrogen bond between tetrandrine and HDAC3/8

and all docking sites were docked by 4 active amino acids. Three small molecules (ursolic acid

fangchinoline and tetrandrine) with the best docking effect had the inhibitory activity against HDAC3/8 at the concentration of 500 μmol·L

-1

and 100 μmol·L

-1

and the inhibitory activity was still optimal among the 10 selected small molecules.

Conclusion:

Among the screened 19 small molecules

ursolic acid

tetrandrine and fangchinoline may be the new anti-inflammatory drugs of HDAC3/8 inhibitory target

which provides a reference for further exploration and discovery of new anti-inflammatory drugs.

关键词

Keywords

references

王秋实．基于NF- κ B和MAPK通路的类叶牡丹及其特征成分抗炎机制研究 [D]．哈尔滨：黑龙江中医药大学， 2016 .

L Y KONG , R X TAN ． Artemisinin，a miracle of traditional Chinese medicine [J]． Nat Prod Rep ， 2015 ， 32 ( 12 ): 1617 - 1621 .

E A KOUTSOGIANNOULI ， W A SCHULZ ． Histone Acetyltransferases [M]． Heidelberg ： Springer-Verlag ， 2017 ： 151 .

P A WADE ． Transcriptional control at regulatory checkpoints by histone deacetylases：molecular connections between cancer and chromatin [J]． Hum Mol Genet ， 2001 ， 10 ( 7 ): 693 - 698 .

W D CRESS , E SETO ． Histone deacetylases，transcriptional control，and cancer [J]． J Cell Physiol ， 2000 ， 184 ( 1 ): 1 - 16 .

L J JUAN , W J SHIA , M H CHEN ， et al . Histone deacetylases specifically down-regulate p53-dependent gene activation [J]． J Biol Chem ， 2000 ， 275 ( 27 ): 20436 - 20443 .

H VAZIRI , S K DESSAIN , E NG-EATON ， et al . hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase [J]． Cell ， 2001 ， 107 ( 2 ): 149 - 159 .

A BRUNET , L B SWEENEY , J F STURGILL ， et al . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase [J]． Science ， 2004 ， 303 ( 5666 ): 2011 - 2015 .

C HUBBERT , A GUARDIOLA , R SHAO ， et al . HDAC6 is a microtubule-associated deacetylase [J]． Nature ， 2002 ， 417 ( 6887 ): 455 - 458 .

N A WOLFSON , C PITCAIRN , C A FIERKE ． HDAC8 substrates：histones and beyond [J]． Biopolymers ， 2013 ， 99 ( 2 ): 112 - 126 .

R GLAUBEN , B SIEGMUND ． Molecular basis of histone deacetylase inhibitors as new drugs for the treatment of inflammatory diseases and cancer [J]． Methods Mol Biol ， 2009 ， 512 : 365 - 376 .

E TOUSSIROT , K A KHAN , G HERBEIN ． Histone deacetylase inhibitors：a new and promising drug class for the treatment of arthritis？ [J]． Clin Epigenetics ， 2010 ， 1 ( 1/2 ): 3 - 6 .

刘莹，王振洲，李平亚，等．天然药物抗炎成分及作用机制的研究进展 [J]．特产研究， 2017 ， 39 ( 1 ): 69 - 76 .

张立虎，李冬冬，萧伟，等．基于网络药理学与分子对接法预测银杏叶提取物的抗炎机制 [J]．中国实验方剂学杂志， 2018 ， 24 ( 7 ): 192 - 198 .

吉日木巴图，范娜，王蕊，等．基于分子对接技术探讨残黄片退黄作用机制 [J]．中国实验方剂学杂志， 2019 ， 25 ( 10 ): 154 - 161 .

D M THAL , B SUN , D FENG ， et al . Crystal structures of the M1 and M4 muscarinic acetylcholine receptors [J]． Nature ， 2016 ， 531 ( 7594 ): 335 - 340 .

M S GILARDINI MONTANI , M GRANATO , C SANTONI ， et al . Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells [J]． Cell Oncol(Dordr) ， 2017 ， 40 ( 2 ): 167 - 180 .

Y Z WANG , L LI , S M DENG ， et al . Ursolic acid ameliorates inflammation in cerebral ischemia and reperfusion injury possibly via high mobility group Box 1/Toll-like receptor 4/NF- κ B pathway [J]． Front Neurol ， 2018 ， doi: 10.3389/fneur.2018.00253 http://dx.doi.org/10.3389/fneur.2018.00253 .

刘雁飞，韩盼，赖永继．熊果酸对慢性非细菌性前列腺炎模型大鼠的治疗作用 [J]．医药导报， 2015 ， 34 ( 10 ): 1292 - 1295 .

王蓉，马腾茂，刘飞，等．防己的药理作用及临床应用研究进展 [J]．中国中药杂志， 2017 ， 42 ( 4 ): 634 - 639 .

X LI , Z WU , B HE ， et al . Tetrandrine alleviates symptoms of rheumatoid arthritis in rats by regulating the expression of cyclooxygenase-2 and inflammatory factors [J]． Exp Ther Med ， 2018 ， 16 ( 3 ): 2670 - 2676 .

C ANGIOLILLI , P A KABALA , A M GRABIEC ， et al . Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes [J]． Ann Rheum Dis ， 2017 ， 76 ( 1 ): 277 - 285 .

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