使用人类肝细胞对药物代谢酶的选择性抑制剂进行新型多重复合高通量查
Jianhua Liu1, Daria Vernikovskaya1, Gary Bora1
1Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
The AAPS journal
|March 28, 2024
概括
研究人员开发了一种新的多重复合高吞吐量查 (HTS) 试验,以识别药物代谢酶的选择性抑制剂. 这种新方法显著改善了对药物开发至关重要的酶抑制剂的发现.
科学领域:
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
- 药物发现 药物发现 药物发现
背景情况:
- 选择性化学抑制剂对于反应表型化至关重要,以确定负责药物消除的药物代谢酶.
- 选择性抑制剂对较少常见的P450 (CYP) 和非CYP酶的有限可用性在药物开发中构成了挑战.
研究的目的:
- 开发和验证一个多重的高吞吐量选 (HTS) 试验,用于同时监测多种药物代谢酶的抑制.
- 为了弥补选择性抑制剂的缺口,用于不太常见的药物代谢酶.
主要方法:
- 开发使用20个基质反应在384井格式的多重HTS试验,用于同时监测酶抑制.
- 整合机器人系统和LC-MS/MS仪器仪表,用于高吞吐量分析.
- 虚拟查用于根据现有数据和酶结构识别潜在的抑制剂.
主要成果:
- 该试验成功选了大约4600种化合物,为各种药物代谢酶提供了大量的结果.
- 确定了两种依赖时间和选择性阿尔德海德氧化酶抑制剂:埃洛提尼布和二西奥芬.
- 与传统的HTS相比,在生物点上实现了显著更高的命中率,这归因于酶乱交和化合物选择偏差.
结论:
- 开发的多重HTS试验是首个针对药物代谢酶的试验,提供了更高的吞吐量和效率.
- 该试验有效地确定了新型选择性抑制剂,包括阿尔代氧化酶.
- 未来的工作将专注于识别缺乏质量成功的酶的抑制剂,并彻底描述新发现的抑制剂.
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