从DNA编码小分子库×蛋白库选择中发现一种共价激酶抑制剂
Alix I Chan1, Lynn M McGregor1, Tara Jain1
1The Broad Institute of Harvard and MIT, Howard Hughes Medical Institute, and the Department of Chemistry and Chemical Biology, Harvard University , 75 Ames Street, Cambridge, Massachusetts 02142, United States.
Journal of the American Chemical Society
|July 11, 2017
概括
使用未净化的蛋白质 (IDUP) 确定了新的药物点. 这种方法发现乙酸是MAP2K6激酶抑制剂,验证了IDUP用于生物医学研究.
科学领域:
- 生物化学
- 化学生物学
- 药物发现
背景情况:
- 使用未净化蛋白的相互作用确定 (IDUP) 是一种从复杂的生物混合物中识别DNA编码的配体:目标对的方法.
- 之前的工作确定了IDUP在细胞溶解物中与DNA结合的小分子和未净化的蛋白标的实用性.
研究的目的:
- 应用IDUP对DNA编码生物活性化合物库进行大规模选,以对抗DNA标记的人类激酶.
- 确定新的小分子:蛋白相互作用和潜在的药物候选物.
主要方法:
- 使用溶液相库×库实验,结合DNA编码的生物活性化合物和DNA标记的人类激酶.
- 采用IDUP方法来选择性地放大对应于联体:蛋白结合对的DNA序列.
- 分析了32,096种可能的组合以确定相互作用.
主要成果:
- 成功地回顾了已知的小分子:蛋白相互作用,验证了实验方法.
- 确定乙烯酸作为一种新的MAP2K6激酶配体和抑制剂.
- 确定乙烯酸通过未保存的囊残留物基化抑制MAP2K6.
结论:
- 鉴于IDUP方法能够发现具有重要的生物医学意义的蛋白质的配体,该方法得到了验证.
- 乙酸代表了一类新的MAP2K6抑制剂,具有潜在的治疗应用.
- 促进药物发现和目标识别的高通量选.
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