Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening
Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening
复制标题
通过基于 NMR 片段的筛选鉴定 NSD1 SET 结构域的新命中
DOI：
10.11938/cjmr20182696
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发表时间：
2019-06
影响因子：
--
通讯作者：
Jia Gao
中科院分区：
文献类型：
--
作者：
Heng Tang;Nshogoza Gilbert;Mingqing Liu;Yaqian Liu;Ke Ruan;Rong-sheng Ma;Jia Gao
Nuclear receptor binding SET domain protein 1 (NSD1), which is a family member of histone methyltransferases, functions to methylate histone H3 on lysine 36 (H3K36). NSD1-related abnormalities are the major cause of Sotos syndrome, and also known to be associated with other human diseases. Inhibitors targeting histone methyltransferases DOT1L and EZH2 have been reported recently. However, no chemical probes targeting NSD1 have been found so far. Here, we identified three hits targeting the NSD1 SET domain using ligand-observed nuclear magnetic resonance (NMR) fragment-based screening. The binding affinities of the hit compounds to the NSD1 SET domain were determined by dose-dependent chemical shift perturbation analysis. Furthermore, the potential binding modes of the hit compounds to NSD1 were obtained by molecular docking. The hit compound 1 was found to bind to the binding pocket of S-adenosylmethionine (SAM), an endogenous ligand of the protein, in the NSD1 SET domain. The study provided valuable information for further structure-guided hit-to-lead evolution towards the potent and specific inhibitors of the NSD1 SET domain.
