Small-molecule ligand docking into comparative models with Rosetta.
Small-molecule ligand docking into comparative models with Rosetta.
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DOI：
10.1038/nprot.2013.074
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发表时间：
2013
期刊：
影响因子：
14.8
通讯作者：
Meiler J
中科院分区：
文献类型：
--
作者：
Combs SA;Deluca SL;Deluca SH;Lemmon GH;Nannemann DP;Nguyen ED;Willis JR;Sheehan JH;Meiler J
基于结构的药物设计经常用于加速小分子治疗剂的开发。虽然在X射线晶体学和核磁共振（NMR）光谱学方面取得了重大进展，但由于经常无法结晶或获得足够的NMR限制，大或灵活的蛋白质的高分辨率结构的可用性是有限的。计算方法可以用来预测未知的蛋白质结构和模型配体相互作用时，实验数据不可用。本文描述了一个全面而详细的协议，使用罗塞塔建模套件对接小分子配体到比较模型。在这里提出的协议中，我们回顾了比较建模过程，包括序列比对，线程和循环建设。接下来，我们将介绍将小分子配体对接到蛋白质比较模型中。此外，我们讨论的标准，可以提高配体对接到比较模型。最后，重要的是，我们提出了一个评估模型质量的策略。整个协议是在一个单一的例子中提出的，这个例子仅仅是为了教学的目的而选择的。因此，这些结果并不具有代表性，也不能取代其他地方公布的基准。我们还提供了一个额外的教程，以便用户可以获得使用Rosetta的实践经验。该协议应采取5-7小时，与额外的时间分配给计算机生成的模型。
Structure-based drug design is frequently used to accelerate the development of small-molecule therapeutics. Although substantial progress has been made in X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, the availability of high-resolution structures is limited owing to the frequent inability to crystallize or obtain sufficient NMR restraints for large or flexible proteins. Computational methods can be used to both predict unknown protein structures and model ligand interactions when experimental data are unavailable. This paper describes a comprehensive and detailed protocol using the Rosetta modeling suite to dock small-molecule ligands into comparative models. In the protocol presented here, we review the comparative modeling process, including sequence alignment, threading and loop building. Next, we cover docking a small-molecule ligand into the protein comparative model. In addition, we discuss criteria that can improve ligand docking into comparative models. Finally, and importantly, we present a strategy for assessing model quality. The entire protocol is presented on a single example selected solely for didactic purposes. The results are therefore not representative and do not replace benchmarks published elsewhere. We also provide an additional tutorial so that the user can gain hands-on experience in using Rosetta. The protocol should take 5–7 h, with additional time allocated for computer generation of models.
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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