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首页> 外文期刊>BMC Genomics >FReDoWS: a method to automate molecular docking simulations with explicit receptor flexibility and snapshots selection
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FReDoWS: a method to automate molecular docking simulations with explicit receptor flexibility and snapshots selection

机译：FReDoWS：一种具有明显受体灵活性和快照选择的自动化分子对接模拟的方法

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BackgroundIn silico molecular docking is an essential step in modern drug discovery when driven by a well defined macromolecular target. Hence, the process is called structure-based or rational drug design (RDD). In the docking step of RDD the macromolecule or receptor is usually considered a rigid body. However, we know from biology that macromolecules such as enzymes and membrane receptors are inherently flexible. Accounting for this flexibility in molecular docking experiments is not trivial. One possibility, which we call a fully-flexible receptor model, is to use a molecular dynamics simulation trajectory of the receptor to simulate its explicit flexibility. To benefit from this concept, which has been known since 2000, it is essential to develop and improve new tools that enable molecular docking simulations of fully-flexible receptor models.ResultsWe have developed a Flexible-Receptor Docking Workflow System (FReDoWS) to automate molecular docking simulations using a fully-flexible receptor model. In addition, it includes a snapshot selection feature to facilitate acceleration the virtual screening of ligands for well defined disease targets. FReDoWS usefulness is demonstrated by investigating the docking of four different ligands to flexible models of Mycobacterium tuberculosis’ wild type InhA enzyme and mutants I21V and I16T. We find that all four ligands bind effectively to this receptor as expected from the literature on similar, but wet experiments.ConclusionsA work that would usually need the manual execution of many computer programs, and the manipulation of thousands of files, was efficiently and automatically performed by FReDoWS. Its friendly interface allows the user to change the docking and execution parameters. Besides, the snapshot selection feature allowed the acceleration of docking simulations. We expect FReDoWS to help us explore more of the role flexibility plays in receptor-ligand interactions. FReDoWS can be made available upon request to the authors.
机译：背景技术当受到明确定义的大分子靶标驱动时，计算机分子对接是现代药物发现中必不可少的步骤。因此，该过程称为基于结构或合理的药物设计（RDD）。在RDD的对接步骤中，大分子或受体通常被视为刚体。但是，从生物学上我们知道，诸如酶和膜受体之类的大分子具有固有的柔韧性。在分子对接实验中考虑这种灵活性并非易事。一种称为全柔性受体模型的可能性是，使用受体的分子动力学模拟轨迹来模拟其显式柔性。为了受益于这个自2000年就已广为人知的概念，开发和改进能够对全柔性受体模型进行分子对接模拟的新工具至关重要。结果我们已经开发了一种柔性受体对接工作流系统（FReDoWS），以使分子自动化使用完全灵活的接收器模型进行对接模拟。此外，它还包括快照选择功能，可促进加速对定义明确的疾病目标的配体进行虚拟筛选。通过研究四种不同配体与结核分枝杆菌野生型InhA酶以及突变体I21V和I16T的灵活模型对接，证明了FReDoWS的有效性。我们发现所有四个配体均有效地结合了该受体，这是类似但湿实验中文献所期望的。结论有效且自动执行了通常需要手动执行许多计算机程序并处理数千个文件的工作由FReDoWS。其友好的界面允许用户更改对接和执行参数。此外，快照选择功能还可以加速对接仿真。我们希望FReDoWS能够帮助我们探索灵活性在受体-配体相互作用中的更多作用。可根据要求向作者提供FReDoWS。

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