Zhong Hai-Jing, Leung Ka-Ho, Lin Sheng, Chan Daniel Shiu-Hin, Han Quan-Bin, Chan Sharon Lai-Fung, Ma Dik-Lung, Leung Chung-Hang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Methods. 2015 Jan;71:71-6. doi: 10.1016/j.ymeth.2014.08.014. Epub 2014 Sep 4.
NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.
NEDD8激活酶（NAE）控制由cullin-RING泛素E3连接酶调节的蛋白质的特异性降解，并且已被视为开发抗癌药物的一个有吸引力的分子靶点。由一组去氧瓦西酮衍生物训练集构建的药效团模型用于从类似物数据库中筛选376种化合物。从初步筛选中，缬氨酸连接的去氧瓦西酮衍生物9和N-异丙基连接的去氧瓦西酮衍生物10成为得分最高的候选物。化合物9和10在无细胞和基于细胞的系统中均显示出微摩尔级别的效力，对NAE的选择性高于相关酶SAE和UAE。分子建模分析表明，9和10可能通过阻断ATP结合域来抑制NAE。因此，这些去氧瓦西酮衍生物可被视为开发更有效NAE抑制剂的有前景的先导分子。
