Evidence map›Paper›PMID 37398436›Full record

ArticlebioRxiv : the preprint server for biology2023

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

Philipp Trepte, Christopher Secker, Simona Kostova, Sibusiso B Maseko, Soon Gang Choi, Jeremy Blavier, Igor Minia, Eduardo Silva Ramos, Patricia Cassonnet, Sabrina Golusik and 17 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 5 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 9 institutions in 6 countries.

Philipp TrepteProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Christopher SeckerProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Simona KostovaProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Sibusiso B MasekoLaboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
Soon Gang ChoiCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Jeremy BlavierLaboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
Igor MiniaRNA Biology and Posttranscriptional Regulation, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125, Berlin, Germany.
Eduardo Silva RamosProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Patricia CassonnetDépartement 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.
Sabrina GolusikProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Martina ZenknerProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Stephanie BeetzProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Mara J LiebichProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Nadine ScharekProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Anja SchützProtein Production & Characterization, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Marcel SperlingMultifunctional Colloids and Coating, Fraunhofer Institute for Applied Polymer Research (IAP), 14476, Potsdam-Golm, Germany.
Michael LisurekStructural Chemistry and Computational Biophysics, Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125, Berlin, Germany.
Yang WangCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Kerstin SpirohnCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Tong HaoCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Michael A CalderwoodCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
David E HillCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Markus LandthalerRNA Biology and Posttranscriptional Regulation, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125, Berlin, Germany.
Julien OlivetLaboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
Jean-Claude TwizereLaboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
Marc VidalCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Erich E WankerProteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
Max Delbrück Center · DEHarvard University · USUniversity of Liège · BECentre National de la Recherche Scientifique · FRFraunhofer Institute for Applied Polymer Research · DEInstitute of Molecular Biotechnology · ATLeibniz-Forschungsinstitut für Molekulare Pharmakologie · DENew York University Abu Dhabi · AEZuse Institute Berlin · DE

Funding

Genomic Analysis of Network Perturbations in Human DiseaseP50HG004233 · NHGRI · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2007 to 2017
$31.6M
Resource ProjectU41HG001715 · NHGRI · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2015 to 2017
$4.7M
Interface-resolution domain-domain interactome map of the yeast complexomeR01GM130885 · NIGMS · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2019 to 2022
$2.7M
NHGRI NIH HHS P50 HG004233NHGRI NIH HHS U41 HG001715NIGMS NIH HHS R01 GM130885
6 · The paper itself

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.

Indexed as

AlphaFoldmachine learningprotein-protein interactionsSARS-CoV-2VirtualFlow

Identifiers

PMID37398436
PMCPMC10312674
OpenAlexW4380589697

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.