用天然产品调节NRF2/KEAP1-介导的氧化应激以治疗癌症,使用基于药的查,分子对接和分子动力学研究
Abdulrahim A Alzain1, Rua M Mukhtar1, Nihal Abdelmoniem1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan.
Molecules (Basel, Switzerland)
|August 26, 2023
概括
这项研究确定了针对KEAP1的天然化合物,以激活对抗癌症至关重要的Nrf2抗氧化途径. 三种有前途的化合物通过抑制Keap1-Nrf2蛋白质-蛋白质相互作用,显示出作为新型癌症治疗药物的潜力.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 氧化应激是癌症发展的关键因素.
- Keap1-Nrf2蛋白与蛋白相互作用 (PPI) 抑制了Nrf2抗氧化途径.
- 针对这种PPI是一种有前途的癌症治疗策略.
研究的目的:
- 确定抑制Keap1-Nrf2 PPI的天然化合物.
- 利用以结构为基础的药物设计,针对KEAP1凯尔奇域.
主要方法:
- 构建了KEAP1抑制剂复合物的药模型.
- 选了6178种化合物,随后进行了对接和MM/GBSA分析.
- 进行了联结体-残留物相互作用,ADMET和分子动力学模拟.
主要成果:
- 确定了10种比KEAP1.1具有更高的结合能量的化合物.
- 选择了三个化合物 (ZINC000002123788,ZINC000002111341,ZINC000002125904) 进行进一步研究.
- 证实了有利的类似药物的特性和稳定的配体-蛋白质复合体形成.
结论:
- 选择的天然化合物显示出准KEAP1.1的潜力.
- 这些化合物可以作为癌症治疗的新型治疗剂.
- 为未来的实验验证和药物开发提供了基础.
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