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发现双重向的GSK-3β/HIV-1逆转录酶抑制剂作为神经保护性抗病毒剂

Thane Jones¹, Renuka Raman¹, Ana C Puhl¹

¹Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.

ACS chemical neuroscience

|December 12, 2024

概括

研究人员选抗病毒药物用于抑制糖原合成酶激酶-3β (GSK-3β),发现埃特拉维林和里尔皮维林具有活性. 确定了一种强大的GSK-3β抑制剂,以及用于未来药物优化的机器学习模型.

科学领域:

生物化学和药理学生物化学和药理学
神经科学和药物发现

背景情况:

糖原合成酶激酶-3β (GSK-3β) 是一种关键激酶,与阿尔茨海默病和艾滋病相关痴呆症 (HAD) 等神经系统疾病有关.
艾滋病毒-1感染中的GSK-3β上调有助于神经元功能障碍,突出显示了对GSK-3β和HIV-1逆转录酶的双重抑制剂的必要性,以进行神经保护.
目前,没有GSK-3β抑制剂得到批准,因此需要探索新型治疗剂.

研究的目的:

选一组抗病毒化合物对抗GSK-3β.的抑制活性.
确定具有HIV-1患者神经保护疗法潜力的新型GSK-3β抑制剂.
开发和验证用于预测GSK-3β抑制的机器学习模型.

主要方法:

针对GSK-3β.各种抗病毒化合物的查.
确定已识别的抑制剂的IC50值的确定.
针对GSK-3β抑制的机器学习模型的生成和验证.

主要成果:

经批准的药物埃特拉维林和里尔皮维林表现出GSK-3β抑制活性,IC50值分别为619nM和502nM.
三种化合物 (11726169,12326205,12326207) 被确定为IC50<1微米.
化合物11726169成为最强大的抑制剂,其体外IC50为12.1nM. 机器学习模型被成功验证.

结论:

埃特拉维林和里尔皮维林表现出以前未被识别的GSK-3β抑制活性.
化合物11726169是一种具有治疗潜力的高强度GSK-3β抑制剂.
机器学习模型为未来优化GSK-3β抑制剂提供了一个有希望的方法.

关键词:

这是阿尔茨海默氏症.在CNS中,CNS是CNS.这是GSK-3ββ.艾滋病病毒艾滋病病毒艾滋病病毒机器学习是机器学习.神经保护神经保护

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