Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library
Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library
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DOI：
10.1021/acsmedchemlett.5b00179
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发表时间：
2015-08-01
影响因子：
4.2
通讯作者：
Zhou, Quan
中科院分区：
文献类型：
--
作者：
Deng, Hongfeng;Zhou, Jingye;Zhou, Quan
作为肥胖症的潜在靶标，针对超过140亿个DNA编码的不同支架化合物筛选人BCATm，然后进行脱DNA合成和活性确认。因此，发现了几个系列的BCATm抑制剂。一种代表性化合物（R）-34（1-（5-溴噻吩-2-羰基）-吡咯烷-3-基）氧基）-N-甲基-2 '-（甲基磺酰氨基）-[1，1'-联苯基]-4-甲酰胺（15 e）来自通过DNA上Suzuki-Miyaura交叉偶联合成的新化合物文库，显示出BCATm抑制活性，IC 50 = 2.0 μ M。15 e的蛋白质晶体结构显示，它在邻近PLP辅因子的催化位点内与BCATm结合。这种新型抑制剂系列的鉴定以及BCATm蛋白结构的建立为未来基于结构的BCATm抑制剂发现提供了良好的起点。
As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-34(1-(5-bromothiophene-2-carbonyl)-pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'- biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 mu M. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.