Philipp Trepte, Christopher Secker, Julien Olivet, Jeremy Blavier, Simona Kostova, Sibusiso B Maseko, Igor Minia, Eduardo Silva Ramos, Patricia Cassonnet, Sabrina Golusik, Martina Zenkner, Stephanie Beetz, Mara J Liebich, Nadine Scharek, Anja Schütz, Marcel Sperling, Michael Lisurek, Yang Wang, Kerstin Spirohn, Tong Hao, Michael A Calderwood, David E Hill, Markus Landthaler, Soon Gang Choi, Jean-Claude Twizere, Marc Vidal, Erich E Wanker
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引用次数: 0
摘要
蛋白质-蛋白质相互作用(PPIs)为扩大可药用蛋白质组和治疗各种疾病提供了巨大的机会,但仍然是药物发现的挑战性靶点。在这里,我们提供了一个结合实验和计算工具的综合管道,用于识别和验证 PPI 靶点并进行早期药物发现。我们开发了一种机器学习方法,通过分析来自二元 PPI 检测或 AlphaFold-Multimer 预测的定量数据来确定相互作用的优先次序。利用定量检测 LuTHy 和我们的机器学习算法,我们确定了 SARS-CoV-2 蛋白质之间的高置信度相互作用,我们使用 AlphaFold-Multimer 预测了这些蛋白质的三维结构。我们利用 VirtualFlow,通过超大规模虚拟药物筛选,锁定了 NSP10-NSP16 SARS-CoV-2 甲基转移酶复合物的接触界面。因此,我们找到了一种化合物,它能与 NSP10 结合并抑制其与 NSP16 的相互作用,同时还能破坏复合物的甲基转移酶活性以及 SARS-CoV-2 的复制。总之,这条研究路线将有助于确定 PPI 靶点的优先次序,从而加速发现以蛋白质复合物和通路为靶点的早期候选药物。
AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
Protein-protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays or AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold-Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.
期刊介绍:
Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems.
Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.