Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase
Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase
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DOI：
10.1021/jm060429m
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发表时间：
2006-10-05
影响因子：
7.3
通讯作者：
Hol, Wim G. J.
中科院分区：
文献类型：
--
作者：
Bosch, Jurgen;Robien, Mark A.;Hol, Wim G. J.
2.4.2.6用SAD（a）定相法测定了布氏锥虫核苷2-脱氧核糖基转移酶（TbNDRT）的1.8埃解析度的nouo结构。这种酶在核苷再循环的补救途径中很重要。为了鉴定新的先导化合物，我们利用“片段鸡尾酒浸泡”。在31种鸡尾酒中尝试的304种化合物中，有4种化合物可以在活性部位进行晶体学鉴定。此外，我们证明，非常短的浸泡类似于10秒是足够的，甚至相当疏水的配体结合在活性位点的凹槽，这是有希望的应用程序类似的浸泡实验，其他蛋白质的不太强大的晶体。
The 1.8 angstrom resoultion de nouo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SAD(a) phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel lead compounds, we exploited "fragment cocktail soaks". Out of 304 compounds tried in 31 cocktails, four compounds could be identified crystallographically in the active site. In addition, we demonstrated that very short soaks of similar to 10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove, which is promising for the application of similar soaking experiments to less robust crystals of other proteins.