AlphaFold; Machine Learning; Protein–Protein Interactions; SARS-CoV-2; VirtualFlow; Methyltransferases; Humans; Methyltransferases/metabolism; Artificial Intelligence; Drug Discovery; SARS-CoV-2/metabolism; COVID-19; Applied Mathematics; Computational Theory and Mathematics; General Agricultural and Biological Sciences; General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; Information Systems
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Trepte, Philipp ✱; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany. philipp.trepte@imba.oeaw.ac.at ; Brain Development and Disease, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030, Vienna, Austria. philipp.trepte@imba.oeaw.ac.at
Secker, Christopher ✱; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany. secker@zib.de ; Zuse Institute Berlin, Berlin, Germany. secker@zib.de
Olivet, Julien ✱; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network ; 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
Blavier, Jeremy ✱; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network
Kostova, Simona; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Minia, Igor; RNA Biology and Posttranscriptional Regulation, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125, Berlin, Germany
Silva Ramos, Eduardo ; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Cassonnet, Patricia; 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, Sabrina; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Zenkner, Martina; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Beetz, Stephanie; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Liebich, Mara J; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Scharek, Nadine; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Schütz, Anja ; Protein Production & Characterization, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
Sperling, Marcel ; Multifunctional Colloids and Coating, Fraunhofer Institute for Applied Polymer Research (IAP), 14476, Potsdam-Golm, Germany
Lisurek, Michael ; Structural Chemistry and Computational Biophysics, Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125, Berlin, Germany
Wang, Yang; 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, Kerstin; 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, Tong; 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, Michael A ; 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, David E ; 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, Markus ; 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
Choi, Soon Gang ; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA. soongangchoi@gmail.com ; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA. soongangchoi@gmail.com ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. soongangchoi@gmail.com
Twizere, Jean-Claude ✱; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network
Vidal, Marc ✱; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA. marc_vidal@dfci.harvard.edu ; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA. marc_vidal@dfci.harvard.edu
Wanker, Erich E ✱; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany. erich.w@mdc-berlin.de
LabEx IBEID (Biologie Intégrative des Maladies Infectieuses Emergentes)
Funders :
BMBF - Bundesministerium für Bildung und Forschung HGF - Helmholtz Association of German Research Centres CHDI Foundation DKTK - Deutschen Konsortium für Translationale Krebsforschung DFG - Deutsche Forschungsgemeinschaft F.R.S.-FNRS - Fonds de la Recherche Scientifique WBI - Wallonia-Brussels International NIH - National Institutes of Health Deutsche Krebshilfe
Funding number :
Claudia Adams Barr Award; Wallonia-Brussels International (WBI)-World Excellence Fellowship
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