使用声射质谱进行高通量共价变量选
Xiujuan Wen1, Chang Liu2, Kiersten Tovar1
1Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Journal of the American Chemical Society
|July 12, 2024
概括
高分辨率的声喷射质谱 (AEMS) 能够快速,高通量选共价变量. 这种创新平台通过有效地识别功能共价药物候选物来加速药物发现.
科学领域:
- 分析化学
- 药物发现
- 生物化学
背景情况:
- 协同作用的药物提供了一种有前途的策略,
- 传统的质谱法 (例如LC-MS,SPE-MS) 是由于速度和样品制备的限制而导致高通量选的瓶.
- 需要更快,更高效的平台来选大型化合物库的共价结合剂.
研究的目的:
- 引入和评估一个高分辨率的声学弹射质谱 (AEMS) 系统的原型,用于对共价变量器进行高通量选.
- 评估AEMS的可行性,以分析复杂的样本,并进行最少的准备.
- 将AEMS的性能与共价变量选的传统质谱技术进行比较.
主要方法:
- 一种高分辨率声弹质谱 (AEMS) 系统的原型开发.
- 对1536井格式的50kDa目标蛋白 (维纳综合征酶) 选大约10,000个共价修饰剂库.
- 在没有清理的高盐缓冲剂中直接分析样品,然后对共价蛋白-连接物添加物进行自动化数据分析.
主要成果:
- AEMS系统在17小时内完成了大约1万种化合物的选.
- 选显示高准确性,Z'系数为0.8和命中率为2.3%.
- 在随后的生化测试中,75%的确诊结果被证实为功能抗剂,与LC-MS相比,AEMS的虚假阳性/阴性率较低.
结论:
- 原型的AEMS平台能够对共价变量器进行强大的高通量选.
- 与现有方法相比,AEMS显著增加了吞吐量 (10-100倍) 和图书馆大小容量,同时尽量减少样本准备.
- 这种创新方法加快了对具有挑战性的治疗点的功能共价药物候选者的鉴定.
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