基于环生物异构体的多位ChEs-MAO B抑制剂的基于结构的设计:ACHE/BChE选择性切换器和类似药物的特征化
Gabriella La Spada1, Daniela Valeria Miniero2, Mariagrazia Rullo1
1Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy.
新的烯基化合物显示出作为乙胆酶 (AChE) 和单胺氧化酶B (MAO B) 的双抑制剂的前景,可能治疗神经退行性疾病. 这些候选药物还表现出神经保护性质和血脑屏障透.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 药物设计 药物设计
背景情况:
- 库马林衍生物以前被确定为乙胆酶 (AChE) 和单胺氧化酶B (MAO B) 的双抑制剂.
- 提高类似药物的特性和选择性仍然是开发有效神经保护剂的关键挑战.
研究的目的:
- 设计和合成新型氨酸衍生物,其中包括环异环生物异构体.
- 研究这些新化合物的结构-活性关系 (SAR) 和选择性概况,以对比ACHE和MAO B.
- 评估有前途的候选人的神经保护潜力和血脑屏障 (BBB) 透率.
主要方法:
- 基于结构的药物设计,将基于蒂奥芬的生物异构剂纳入库马林支架中.
- 酶抑制试验用于确定ACHE,MAO B和丁烯醇化酶 (BChE) 的IC50值.
- 平行人工膜透性测试 (PAMPA-HDM) 用于膜透性的评估.
- 使用SH-SY5Y细胞进行基于细胞的测试,以评估对氧化损伤 (H2O2和6-OHDA) 的保护.
- 在血脑屏障透的in silico预测.
- 分子动力学 (MD) 模拟以阐明酶-抑制剂相互作用.
主要成果:
- 基于蒂奥芬的异素7和15被确定为具有强大的双重ACH-MAO B和BCHE-MAO B抑制剂,具有纳米IC50值.
- 化合物7和15显示中等水溶性和膜透性.
- 这两种化合物都在SH-SY5Y细胞中表现出对氧化应激的神经保护作用.
- 在模型中预测了化合物7和15的中枢神经系统透率.
- MD模拟显示了AChE和BChE活性位点内的不同的结合模式和相互作用,受链接器长度的影响.
结论:
- 基于蒂奥芬的库马林衍生物代表了一类有前途的双重ACHE-MAO B抑制剂,在神经退行性疾病中具有潜在的治疗应用.
- 已识别的化合物具有有利的类似药物的特性,包括神经保护和BBB透能力.
- 基于SAR和MD洞察力的进一步优化可能会导致开发新的中枢神经系统活性剂.
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