使用人工智能来识别药物用于治疗l-DOPA诱导的运动障碍
Tom H Johnston1, Alix M B Lacoste2, Paula Ravenscroft1
1Atuka Inc, Suite 5600, 100 King St. W. Toronto, Ontario, M5X 1C9, Canada.
Neuropharmacology
|February 27, 2024
概括
将现有的药物用于帕金森病治疗的重用显示出有前途. 一个in silico屏幕确定了lorcaserin,acamprosate和ganaxolone对l-DOPA诱导的动力障碍,但在动物模型中,只有lorcaserin显示了部分有效性.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 计算生物学 计算生物学
背景情况:
- 药物重定向提供了一个更快,更安全的新疗法路线.
- 帕金森病的治疗往往涉及l-DOPA,这可能会导致衰弱的运动并发症,如l-DOPA诱导的动力障碍 (LID).
- 鉴定LID的新型治疗方法是帕金森病管理中的关键未满足需求.
研究的目的:
- 以计算方式选现有药物对l-DOPA诱导的运动障碍 (LID) 的潜在有效性.
- 通过in silico方法确定候选药物的临床前评估.
- 评估使用计算方法来加速神经系统疾病的药物发现的可行性.
主要方法:
- 在超过一百万个Medline摘要上使用自然语言处理来对3539种药物进行LID治疗潜力排名.
- 根据新性,缺乏先前的LID验证,生物可用性和临床准备性,优先考虑排名前列的药物 (洛卡塞林,阿坎普罗沙特,加纳克索隆).
- 在动物模型中评估了l-DOPA诱导过活性的药物疗效,以及在MPTP受损的功能障碍上评估了药物疗效.
主要成果:
- 洛卡赛林在动物中减少了58%的旋转不对称性,并在子中减少了82%的LID.
- 在动物模型中,阿坎普酸和加纳克索隆没有显示出显著的疗效.
- 虽然有效降低LID,但卡西林也增加了的帕金森症残疾,阻止其使用.
结论:
- 测试中的药物 (洛卡塞林,阿坎普罗沙特,加纳克索隆) 不适合重新用于治疗LID.
- 该研究验证了 in silico选与 in vivo 测试相结合的有用性,用于识别和降低候选药物的风险.
- 这种方法支持药物重定向的神经疾病的范式转变,如帕金森氏症.
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