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基于结构的通用药物发现神经网络评分函数及其具有可解释药效团图的

General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps.

机构信息

Chemical and Physical Biology Program, Medical Scientist Training Program, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.

Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.

出版信息

J Chem Inf Model. 2021 Feb 22;61(2):603-620. doi: 10.1021/acs.jcim.0c01001. Epub 2021 Jan 26.

Abstract

The BioChemical Library (BCL) is an academic open-source cheminformatics toolkit comprising ligand-based virtual high-throughput screening (vHTS) tools such as quantitative structure-activity/property relationship (QSAR/QSPR) modeling, small molecule flexible alignment, small molecule conformer generation, and more. Here, we expand the capabilities of the BCL to include structure-based virtual screening. We introduce two new score functions, BCL-AffinityNet and BCL-DockANNScore, based on novel distance-dependent signed protein-ligand atomic property correlations. Both metrics are conventional feed-forward dropout neural networks trained on the new descriptors. We demonstrate that BCL-AffinityNet is one of the top performing score functions on the comparative assessment of score functions 2016 affinity prediction and affinity ranking tasks. We also demonstrate that BCL-AffinityNet performs well on the CSAR-NRC HiQ I and II test sets. Furthermore, we demonstrate that BCL-DockANNScore is competitive with multiple state-of-the-art methods on the docking power and screening power tasks. Finally, we show how our models can be decomposed into human-interpretable pharmacophore maps to aid in hit/lead optimization. Altogether, our results expand the utility of the BCL for structure-based scoring to aid small molecule discovery and design. BCL-AffinityNet, BCL-DockANNScore, and the pharmacophore mapping application, as well as the remainder of the BCL cheminformatics toolkit, are freely available with an academic license at the BCL Commons site hosted on http://meilerlab.org/.

摘要

生物化学文库(BCL)是一个学术性的开源化学信息学工具包,包含基于配体的虚拟高通量筛选(vHTS)工具,如定量构效关系/性质关系(QSAR/QSPR)建模、小分子柔性对准、小分子构象生成等。在这里,我们扩展了 BCL 的功能,包括基于结构的虚拟筛选。我们引入了两种新的评分函数,BCL-AffinityNet 和 BCL-DockANNScore,它们基于新的距离相关的有符号蛋白-配体原子属性相关性。这两个指标都是基于新描述符训练的传统前馈随机失活神经网络。我们证明 BCL-AffinityNet 在 2016 年亲和力预测和亲和力排序任务的评分函数比较评估中是表现最好的评分函数之一。我们还证明了 BCL-AffinityNet 在 CSAR-NRC HiQ I 和 II 测试集上表现良好。此外,我们证明了 BCL-DockANNScore 在对接能力和筛选能力任务上与多种最先进的方法具有竞争力。最后,我们展示了如何将我们的模型分解为可解释的药效团图谱,以帮助命中/先导优化。总之,我们的结果扩展了 BCL 用于基于结构的评分的用途,以帮助小分子的发现和设计。BCL-AffinityNet、BCL-DockANNScore 以及药效团映射应用程序,以及 BCL 化学信息学工具包的其余部分,都可以在学术许可证下免费获得,网址为 BCL Commons 站点,位于 http://meilerlab.org/。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46a7/7903419/1ebd9c10a12a/ci0c01001_0002.jpg

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