AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.

Autor:	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.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 14. Date of Electronic Publication: 2023 Jun 14.
DOI:	10.1101/2023.06.14.544560
Abstrakt:	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.
Databáze:	MEDLINE
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