Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking

Shi-yu ZHAO; Yu-tian LIU; Bing-you YANG; Yan LIU; Shao-wa LYU

doi:10.13422/j.cnki.syfjx.20192446

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Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking

Data Mining | 更新时间：2021-02-09

- Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 26, Issue 7, Pages: 186-194(2020)
- 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：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20192446
  CLC： R22; R24; R28; C37; Q512
- Received：04 July 2019，
  
  Published Online：27 August 2019，
  
  Published：05 April 2020
- 稿件说明：
移动端阅览
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：

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

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