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
{"title":"AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.","authors":"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","doi":"10.1038/s44320-024-00019-8","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"428-457"},"PeriodicalIF":8.5000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987651/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Systems Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44320-024-00019-8","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.