基于片段的核磁共振筛选方法识别NSD1 SET结构域的全新苗头化合物

doi:10.11938/cjmr20182696

波谱学杂志 ›› 2019, Vol. 36 ›› Issue (2): 148-154.doi: 10.11938/cjmr20182696

基于片段的核磁共振筛选方法识别NSD1 SET结构域的全新苗头化合物

汤衡², Gilbert NSHOGOZA¹, 刘明清¹, 刘亚茜¹, 阮科¹, 马荣声¹, 高佳¹

1. 合肥微尺度物质科学国家实验室, 中国科学技术大学生命科学学院, 安徽合肥 230027;
2. 皖北煤电集团总医院, 安徽宿州 234011

收稿日期:2018-11-30 发布日期:2018-12-14
通讯作者: 高佳 Tel:18256925385, E-mail:jiagao@ustc.edu.cn E-mail:jiagao@ustc.edu.cn
基金资助:
National Key R&D Program of China (2016YFA0500700); the National Natural Science Foundation of China (21874123, 21703254, U1632153, 21807095).

Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening

TANG Heng², Gilbert NSHOGOZA¹, LIU Ming-qing¹, LIU Ya-qian¹, RUAN Ke¹, MA Rong-sheng¹, GAO Jia¹

1. Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China;
2. General Hospital of Wanbei Coal-electric Group, Suzhou 234011, China

Received:2018-11-30 Published:2018-12-14
Supported by:
National Key R&D Program of China (2016YFA0500700); the National Natural Science Foundation of China (21874123, 21703254, U1632153, 21807095).

摘要/Abstract

摘要： 包含SET结构域的核受体结合蛋白1（NSD1）是一种组蛋白甲基转移酶，它能够特异性的甲基化组蛋白H3赖氨酸第36位（H3K36）.异常表达的NSD1主要发现于Sotos综合症患者体内，但它同样也能导致其他多种人类疾病的发生.目前已有靶向组蛋白甲基转移酶DOT1L和EZH2的小分子抑制剂报道，然而，靶向NSD1的化学探针分子尚未被发现.本文使用基于片段的核磁共振（NMR）筛选方法寻找到3个以NSD1蛋白作为靶点的苗头化合物，利用化学位移扰动分析技术测定了这些化合物与NSD1的结合亲和力.另外，利用分子对接方法选择获得苗头化合物与NSD1蛋白的最可能的结合模型.结果显示苗头化合物1结合于NSD1天然底物S-腺苷酸甲硫氨酸（SAM）的结合口袋中.我们的研究成果为进一步以结构为指导的从苗头化合物到先导化合物的衍化奠定了基础.

关键词: NSD1 SET结构域, 基于片段的核磁共振筛选, 化学位移扰动, 分子对接

Abstract: 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.

Key words: NSD1 SET domain, NMR fragment-based screening, chemical shift perturbation, molecular docking

中图分类号:

O482.53

汤衡, Gilbert NSHOGOZA, 刘明清, 刘亚茜, 阮科, 马荣声, 高佳. 基于片段的核磁共振筛选方法识别NSD1 SET结构域的全新苗头化合物[J]. 波谱学杂志, 2019, 36(2): 148-154.

TANG Heng, Gilbert NSHOGOZA, LIU Ming-qing, LIU Ya-qian, RUAN Ke, MA Rong-sheng, GAO Jia. Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening[J]. Chinese Journal of Magnetic Resonance, 2019, 36(2): 148-154.

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基于片段的核磁共振筛选方法识别NSD1 SET结构域的全新苗头化合物

Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening

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