Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase
Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase
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DOI：
10.1016/j.bmcl.2013.04.001
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发表时间：
2013-06-01
影响因子：
2.7
通讯作者：
Zhang, Xuying
中科院分区：
文献类型：
--
作者：
Dragovich, Peter S.;Fauber, Benjamin P.;Zhang, Xuying
通过高通量筛选鉴定了一种新的含2-硫代-6-氧代-1，6-二氢嘧啶的人乳酸脱氢酶（LDH）抑制剂（IC 50 = 8.1 μ M）。生物化学、表面等离子体共振和饱和转移差NMR实验表明，该化合物以需要同时结合NADH辅因子的方式与人LDHA特异性结合。筛选命中的结构变化导致LDHA生化抑制活性的显著改善（最佳IC 50 = 0.48 μ M）。获得了与人LDHA结合的优化化合物的晶体结构，并解释了许多观察到的结构-活性关系。(C)2013爱思唯尔有限公司保留所有权利。
A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50 = 8.1 mu M). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.48 mu M). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships. (C) 2013 Elsevier Ltd. All rights reserved.