Blind Docking of 260 Protein-Ligand Complexes with EADock 2.0
Blind Docking of 260 Protein-Ligand Complexes with EADock 2.0
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DOI：
10.1002/jcc.21202
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发表时间：
2009-10-01
影响因子：
3
通讯作者：
Michielin, Olivier
中科院分区：
文献类型：
--
作者：
Grosdidier, Aurelien;Zoete, Vincent;Michielin, Olivier
分子对接软件是现代药物研发管道的重要工具之一。10年来，档案工作取得了可喜的成绩，凸显了进一步改进的必要性。最近的几篇出版物(Leach等人，J Med Chem 2006，49,5851；Warren等人，I Med Chem 2006，49,5912)反映了这一点。我们最初的方法EADock在再现一组37种不同配体-蛋白质复合体的实验结合模式方面表现出很好的性能(Grosdidier等人，Proteins 2007，67,1010)。这篇文章介绍了在评分和采样方面比最初实施的最新改进，以及一个新的基于油的播种程序，用于检测空洞，为与EADock的盲目对接打开了大门。这些增强在取自高质量配基蛋白质数据库[LPDB，(Roche等人，J Med Chem 2001 44,3592)]的260个复合体上得到验证。确定了两个问题：第一，不能假定文件初始结构的质量，可能需要人工检查和/或在文献中搜索才能达到文件的最佳性能。其次，对涉及金属离子的相互作用的描述仍需改进。尽管如此，当只考虑顶级结合模式和2埃RMSD对晶体结构的成功阈值时，大规模盲接实验获得了65%的显著成功率。当查看排名前五的绑定模式时，成功率提高到76%。在标准的局部对接实验中，分别考虑顶级结合模式和活性顶部结合模式，获得了75%和83%的成功率。(C)2009年威利期刊公司J Comput Chem 30：2021-2030,2009
Molecular docking softwares are one of the important tools of modern drug development pipelines. The promising achievements of file last 10 years emphasize the need for further improvement. as reflected by several recent publications (Leach et al., J Med Chem 2006, 49, 585 1; Warren et al., I Med Chem 2006, 49, 5912). Our initial approach, EADock, showed a good performance in reproducing the experimental binding modes for a set of 37 different ligand-protein complexes (Grosdidier et al., Proteins 2007, 67, 1010). This article presents recent improvements regarding the scoring and sampling aspects over the initial implementation, as well as a new seeding procedure based oil the detection of cavities, opening the door to blind docking with EADock. These enhancements were validated on 260 complexes taken from the high quality Ligand Protein Database [LPDB, (Roche et al., J Med Chem 2001 44, 3592)]. Two issues were identified: first, the quality Of file initial Structures cannot be assumed and a manual inspection and/or a search in the literature are likely to be required to achieve file best performance. Second the description of interactions involving metal ions still has to be improved. Nonetheless, a remarkable Success rate of 65% was achieved for a large scale blind docking assay, when considering only the top ranked binding mode and a success threshold of 2 angstrom RMSD to the crystal Structure. When looking at the five-top ranked binding modes, the success rate increases up to 76%. In a standard local docking assay, success rates of 75 and 83% were obtained, considering only the top ranked binding mode, or the live top binding modes, respectively. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 30: 2021-2030, 2009