塞特拉林作为ACHE,COX-2,BACE-1和GSK-3β的多目标调节器:计算和体外研究
Minhajul Arfeen1, Vasudevan Mani2
1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia.
Molecules (Basel, Switzerland)
|November 27, 2024
概括
这项研究确定了塞特拉林作为阿尔茨海默病点的潜在双重抑制剂,包括环氧化原酶-2 (COX-2) 和乙胆酶 (AChE). 在体内研究证实了塞特拉林的存在.
科学领域:
- 神经科学和药理学 神经科学和药理学
- 计算机化药物发现技术
- 生物化学 生物化学
背景情况:
- 阿尔茨海默病 (AD) 涉及关键酶如乙胆酶 (AChE) 和循环氧基酶-2 (COX-2) 的失调.
- 识别针对多个AD相关酶的双重抑制剂对于有效治疗至关重要.
- 机器学习提供了一种强大的方法来选针对多个目标的现有药物.
研究的目的:
- 使用机器学习来选美国FDA批准的药物,以检测AChE和COX-2的潜在双重抑制.
- 评估已识别的化合物对其他与阿尔茨海默病相关的酶的疗效.
- 为了验证化合物在神经炎症体内模型中的治疗潜力.
主要方法:
- 机器学习模型 (随机森林,梯度提升,极端梯度提升) 在ChEMBL数据库数据上训练了ACHE和COX-2的数据.
- 从ZINC15数据库中对美国FDA批准的药物进行虚拟选.
- 进行了分子对接研究和 lipopolysaccharide 诱导的老鼠模型中的体内验证.
主要成果:
- 机器学习模型在预测AChE和COX-2抑制方面达到92-95%的准确性.
- 塞特拉林被确定为AChE和COX-2的潜在双重抑制剂,对AChE,COX-2,BACE-1,GSK-3β和caspase-3具有强烈的结合亲和力.
- 在体内研究显示,塞特拉林显著降低了ACHE,BACE-1,GSK-3β,COX-2,caspase-3和malondialdehyde的水平.
结论:
- 塞特拉林显示出作为阿尔茨海默病多目标治疗剂的潜力.
- 该药物有效地减轻了与AD相关的关键酶活性和病理变化.
- 这项研究强调了机器学习在确定现有药物的新疗法应用中的实用性.
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