학술논문
AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
Document Type
Author
Trepte P; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Brain Development and Disease, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030, Vienna, Austria.; Secker C; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Zuse Institute Berlin, Berlin, Germany.; Kostova S; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Maseko SB; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.; Choi SG; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Blavier J; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.; Minia I; RNA Biology and Posttranscriptional Regulation, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125, Berlin, Germany.; Ramos ES; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Cassonnet P; Département de Virologie, Unité de Génétique Moléculaire des Virus à ARN (GMVR), Institut Pasteur, Centre National de la Recherche Scientifique (CNRS), Université de Paris, Paris, France.; Golusik S; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Zenkner M; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Beetz S; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Liebich MJ; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Scharek N; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Schütz A; Protein Production & Characterization, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.; Sperling M; Multifunctional Colloids and Coating, Fraunhofer Institute for Applied Polymer Research (IAP), 14476, Potsdam-Golm, Germany.; Lisurek M; Structural Chemistry and Computational Biophysics, Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125, Berlin, Germany.; Wang Y; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Spirohn K; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Hao T; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Calderwood MA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Hill DE; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Landthaler M; RNA Biology and Posttranscriptional Regulation, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125, Berlin, Germany.; Institute of Biology, Humboldt-Universität zu Berlin, 13125, Berlin, Germany.; Olivet J; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Structural Biology Unit, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, 3000, Leuven, Belgium.; Twizere JC; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030, Gembloux, Belgium.; Laboratory of Algal Synthetic and Systems Biology, Division of Science and Math, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.; Vidal M; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.; Wanker EE; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Source
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
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 and 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.
Competing Interests: DISCLOSURE AND COMPETING INTERESTS STATEMENT The authors declare that they have no conflict of interest.
Competing Interests: DISCLOSURE AND COMPETING INTERESTS STATEMENT The authors declare that they have no conflict of interest.