Evaluation of docking programs for predicting binding of Golgi α-mannosidase II inhibitors:: A comparison with crystallography
Evaluation of docking programs for predicting binding of Golgi α-mannosidase II inhibitors:: A comparison with crystallography
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DOI：
10.1002/prot.21479
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发表时间：
2007-10-01
影响因子：
2.9
通讯作者：
Moitessier, Nicolas
中科院分区：
文献类型：
--
作者：
Englebienne, Pablo;Fiaux, Helene;Moitessier, Nicolas
高尔基体α-甘露糖苷酶II（GMII）是一种锌依赖性糖基水解酶，是抗肿瘤药物开发的一个有前途的靶点。使用X射线晶体学，我们已经确定了果蝇GMII（dGMII）与三种不同的抑制剂表现出IC 50的范围从80到1000 μ M的复合结构。这些结构，沿着其他七个可用的dGMII/抑制剂复合物的结构，然后用作评估七个对接程序（GOLD，Glide，FlexX，AutoDock，eHiTS，LigandFit和FITTED）的基础。我们发现，小的抑制剂可以被大多数软件准确对接，而较大化合物的对接（即，具有延长的芳环或长脂族链的那些）更成问题。总的来说，Glide提供了最好的对接结果，最准确地预测了活性位点锌原子周围的结合。对Glide性能的进一步评估显示，它有能力从诱饵基准库中提取活性化合物。
Golgi a-mannosidase II (GMII), a zinc-dependent glycosyl hydrolase, is a promising target for drug development in anti-tumor therapies. Using X-ray crystallography, we have determined the structure of Drosophila melanogaster GMII (dGMII) complexed with three different inhibitors exhibiting IC50's ranging from 80 to 1000 mu M. These structures, along with those Of seven other available dGMII/inhibitor complexes, were then used as a basis for the evaluation of seven docking programs (GOLD, Glide, FlexX, AutoDock, eHiTS, LigandFit, and FITTED). We found that small inhibitors could be accurately docked by most of the software, while docking of larger compounds (i.e., those with extended aromatic cycles or long aliphatic chains) was more problematic. Overall, Glide provided the best docking results, with the most accurately predicted binding around the active site zinc atom. Further evaluation of Glide's performance revealed its ability to extract active compounds from a benchmark library of decoys.