DOCK 6: Combining techniques to model RNA-small molecule complexes
DOCK 6: Combining techniques to model RNA-small molecule complexes
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DOI：
10.1261/rna.1563609
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发表时间：
2009-06-01
期刊：
影响因子：
4.5
通讯作者：
Kuntz, Irwin D.
中科院分区：
文献类型：
--
作者：
Lang, P. Therese;Brozell, Scott R.;Kuntz, Irwin D.
随着人们对 RNA 疗法和靶向 RNA 治疗疾病的兴趣日益浓厚，需要对基于蛋白质的药物设计中使用的工具（特别是 DOCKing 算法）进行扩展或适应核酸。在这里，我们编译了一组 RNA-配体复合物测试集，以验证 DOCK 程序套件成功重建实验确定的结合姿势的能力。通过优化的参数和最小的评分函数，70％的具有少于7个可旋转配体键的测试集和26％的具有少于13个可旋转键的测试集可以在2埃重原子RMSD内成功重建。当使用具有溶剂可及表面积 (GB/SA) 的隐式溶剂模型 AMBER 广义 Born 和具有溶剂可及表面积 (PB/SA) 的泊松-玻尔兹曼模型并结合显式水分子和钠抗衡离子对 DOCKed 构象进行重新评分时，对于少于 7 个可旋转键，PB/SA 的成功率增加到 80%，AMBER GB/SA 的成功率增加到 58% 对于少于 13 个可轮换债券，使用 PB/SA 的比例为 47%。这些结果表明 DOCK 确实可用于针对 RNA 的基于结构的药物设计。我们的研究还表明，RNA 导向的配体在静电特性方面通常与典型的蛋白质-配体复合物不同，但这些差异可以通过选择潜在功能来适应。此外，在研究过程中，我们探索了各种新添加的 DOCK 功能，展示了添加新功能以解决新科学问题的轻松性。
With an increasing interest in RNA therapeutics and for targeting RNA to treat disease, there is a need for the tools used in protein-based drug design, particularly DOCKing algorithms, to be extended or adapted for nucleic acids. Here, we have compiled a test set of RNA-ligand complexes to validate the ability of the DOCK suite of programs to successfully recreate experimentally determined binding poses. With the optimized parameters and a minimal scoring function, 70% of the test set with less than seven rotatable ligand bonds and 26% of the test set with less than 13 rotatable bonds can be successfully recreated within 2 angstrom heavy-atom RMSD. When DOCKed conformations are rescored with the implicit solvent models AMBER generalized Born with solvent-accessible surface area (GB/SA) and Poisson-Boltzmann with solvent-accessible surface area (PB/SA) in combination with explicit water molecules and sodium counterions, the success rate increases to 80% with PB/SA for less than seven rotatable bonds and 58% with AMBER GB/SA and 47% with PB/SA for less than 13 rotatable bonds. These results indicate that DOCK can indeed be useful for structure-based drug design aimed at RNA. Our studies also suggest that RNA-directed ligands often differ from typical protein-ligand complexes in their electrostatic properties, but these differences can be accommodated through the choice of potential function. In addition, in the course of the study, we explore a variety of newly added DOCK functions, demonstrating the ease with which new functions can be added to address new scientific questions.