天然产物研究与开发 ›› 2021, Vol. 33 ›› Issue (4): 543-553.doi: 10.16333/j.1001-6880.2021.4.002

• 研究论文 • 上一篇    下一篇

基于计算机模拟技术分析去氢枞酸作为PI3K/AKT/mTOR信号通路抑制剂的潜力

李翠萍1,陈乃源2,4*,李昕宇3,卢国栋2,4   

  1. 1广西医科大学口腔医学院;2广西医科大学公共卫生学院;3广西医科大学基础医学院;4广西高校高发疾病预防与控制研究重点实验室,南宁 530021

  • 出版日期:2021-04-28 发布日期:2021-05-10
  • 基金资助:
    广西自然科学基金(2018GXNSFAA138023);“广西特聘专家”专项(2018)

Analysis of the potentiality of dehydroabietic acid as PI3K/AKT/mTOR signaling pathway inhibitor based on computational simulation

LI Cui-ping1,CHEN Nai-yuan2,4*,LI Xin-yu3,LU Guo-dong2,4   

  1. 1School of Stomatology,Guangxi Medical University;2School of Public Health,Guangxi Medical University;3School of Preclinical Medicine,Guangxi Medical University;4Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases,Guangxi Medical University,Nanning 530021,China

  • Online:2021-04-28 Published:2021-05-10

摘要:

为了研究去氢枞酸对PI3K/AKT/mTOR信号通路的抑制能力,本研究利用分子对接技术预测去氢枞酸对通路蛋白的结合能力和结合方式,用蛋白免疫印迹技术验证通路蛋白受抑制程度,用网络服务器进行类药性与药代动力学的模拟。预测结果发现,去氢枞酸对通路蛋白具有一定的结合能力,预测构像的最低结合能最高为-6.16 kcal/mol;蛋白免疫印迹结果显示,在去氢枞酸作用下,PI3K调控亚基p85的表达明显下调,AKT和mTOR的磷酸化被明显抑制,通路下游磷酸化蛋白的表达也被不同程度的抑制;类药性与药代动力学的模拟发现去氢枞酸通过了大部分的检验。总体上看,去氢枞酸可以作为治疗用PI3K/AKT/mTOR信号通路抑制剂的候选化合物。

关键词: 去氢枞酸, PI3K/AKT/mTOR, 抑制剂, 计算机模拟

Abstract:

To study the inhibitory ability of dehydroabietic acid (DHA) against PI3K/AKT/mTOR signaling pathway,molecular docking was used to predict the binding abilities and the binding modes of DHA with the pathway proteins,western blot was performed to confirm the expressions of the pathway proteins affected by DHA,the “pkCSM-pharmacokinetics” online web-server was chosen for predictions of drug-likeness and pharmacokinetic properties of DHA.The molecular docking results showed that DHA could bind with the pathway proteins because the lowest binding energies of the predicted conformations are not higher than -6.16 kcal/mol.The western blot showed that in the presence of DHA,the expression of p85,the regulatory subunit of PI3K,was decreased obviously;the phosphorylations of AKT and mTOR were inhibited significantly;the expressions of phosphorylated downstream effectors were also inhibited in varying degrees.In the drug-likeness and pharmacokinetic predictions,DHA passes most of the tests.On the whole,DHA may be used as a therapeutic candidate against PI3K/AKT/mTOR signaling pathway.

Key words: dehydroabietic acid, PI3K/AKT/mTOR, inhibitor, computational simulation

中图分类号:  O629.9