AutoPH4: An Automated Method for Generating Pharmacophore Models from Protein Binding Pockets.,Journal of Chemical Information and Modeling

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AutoPH4: An Automated Method for Generating Pharmacophore Models from Protein Binding Pockets.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-07-08 , DOI: 10.1021/acs.jcim.0c00121
Siduo Jiang ₁ , Miklos Feher ₁ , Chris Williams ₂ , Brian Cole ₁ , David E Shaw _{1,

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Affiliation

Pharmacophore models are widely used in computational drug discovery (e.g., in the virtual screening of drug molecules) to capture essential information about interactions between ligands and a target protein. Generating pharmacophore models from protein structures is typically a manual process, but there has been growing interest in automated pharmacophore generation methods. Automation makes feasible the processing of large numbers of protein conformations, such as those generated by molecular dynamics (MD) simulations, and thus may help achieve the longstanding goal of incorporating protein flexibility into virtual screening workflows. Here, we present AutoPH4, a new automated method for generating pharmacophore models based on protein structures; we show that a virtual screening workflow incorporating AutoPH4 ranks compounds more accurately than any other pharmacophore-based virtual screening workflow for which results on a public benchmark have been reported. The strong performance of the virtual screening workflow indicates that the AutoPH4 component of the workflow generates high-quality pharmacophores, making AutoPH4 promising for use in future virtual screening workflows as well, such as ones that use conformations generated by MD simulations.

中文翻译：

AutoPH4：一种从蛋白质结合口袋中生成药效团模型的自动化方法。

药理学模型广泛用于计算药物的发现（例如，在药物分子的虚拟筛选中）以捕获有关配体与靶蛋白之间相互作用的基本信息。从蛋白质结构生成药效团模型通常是手动过程，但是人们对自动药效团产生方法的兴趣日益增长。自动化使处理大量蛋白质构象（例如由分子动力学（MD）模拟生成的构象）成为可能，因此可以帮助实现将蛋白质灵活性纳入虚拟筛选工作流程的长期目标。在这里，我们介绍AutoPH4，这是一种基于蛋白质结构生成药效团模型的新型自动化方法。我们显示，与已报告了公开基准结果的任何其他基于药效团的虚拟筛选工作流程相比，结合了AutoPH4的虚拟筛选工作流程对化合物的排名更为准确。虚拟筛选工作流程的强大性能表明，该工作流程的AutoPH4组件可生成高质量的药效团，这使AutoPH4有望在未来的虚拟筛选工作流程中使用，例如使用MD模拟生成的构象的工作流程。

更新日期：2020-07-08

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