Evidence map›Paper›PMID 33269349›Full record

ArticlebioRxiv : the preprint server for biology2020

Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.

Marion Schuller, Galen J Correy, Stefan Gahbauer, Daren Fearon, Taiasean Wu, Roberto Efraín Díaz, Iris D Young, Luan Carvalho Martins, Dominique H Smith, Ursula Schulze-Gahmen and 43 more

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

Article in bioRxiv : the preprint server for biology, 2020. 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, 41 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

53 authors at 12 institutions in 4 countries.

Marion SchullerSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Galen J CorreyDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.
Stefan GahbauerDepartment of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA.
Daren FearonDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Taiasean WuInstitute for Neurodegenerative Disease, University of California San Francisco, CA, USA.
Roberto Efraín DíazDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.
Iris D YoungDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.
Luan Carvalho MartinsBiochemistry Department, Institute for Biological Sciences, Federal University of Minas Gerais. Belo Horizonte, Brazil.
Dominique H SmithHelen Diller Family Comprehensive Cancer, University of California San Francisco, CA, USA.
Ursula Schulze-GahmenQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Tristan W OwensQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Ishan DeshpandeQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Gregory E MerzQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Aye C ThwinQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Justin T BielQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Jessica K PetersQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Michelle MoritzQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Nadia HerreraQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
Huong T KratochvilQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA.
QCRG Structural Biology Consortium
Anthony AimonDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
James M BennettCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.
Jose Brandao NetoDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Aina E CohenStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.
Alexandre DiasDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Alice DouangamathDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Louise DunnettDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Oleg FedorovCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.
Matteo P FerlaWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.
Martin FuchsNational Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY, USA.
Tyler J Gorrie-StoneDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
James M HoltonDepartment of Biochemistry and Biophysics, University of California San Francisco, CA, USA.
Michael G JohnsonChemPartner Corporation, South San Francisco, CA, USA.
Tobias KrojerCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.
George MeigsDepartment of Biochemistry and Biophysics, University of California San Francisco, CA, USA.
Ailsa J PowellDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Johannes Gregor Matthias Rack
Victor L RangelCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.
Silvia RussiStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.
Rachael E SkynerDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Clyde A SmithStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.
Alexei S SoaresPhoton Sciences, Brookhaven National Laboratory, Upton, NY, USA.
Jennifer L WiermanStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.
Kang ZhuSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Natalia JuraDepartment of Cellular and Molecular Pharmacology, University of California San Francisco, CA, USA.
Alan AshworthHelen Diller Family Comprehensive Cancer, University of California San Francisco, CA, USA.
John IrwinDepartment of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA.
Michael C ThompsonDepartment of Chemistry and Chemical Biology, University of California Merced, CA, USA.
Jason E GestwickiDepartment of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA.
Frank von DelftDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Brian K ShoichetDepartment of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA.
James S FraserDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.
Ivan AhelSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
University of California, San Francisco · USQuantitative BioSciences · USDiamond Light Source · GBUniversity of Oxford · GBSLAC National Accelerator Laboratory · USBrookhaven National Laboratory · USLawrence Berkeley National Laboratory · USCentre for Human Genetics · GBUniversidade de São Paulo · BRUniversidade Federal de Minas Gerais · BRUniversity of California, Merced · USUniversity of Johannesburg · ZA

Funding

X-ray Scattering Technology CoreP30GM133893 · NIGMS · BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB · PI Vivian Stojanoff · 2019 to 2026
$38.6M
X-ray Absorption Spectroscopy (XAS) pp.711-759P41GM103393 · NIGMS · STANFORD UNIVERSITY · PI HODGSON, KEITH O · 2012 to 2019
$30.6M
User Training and OutreachP30GM124169 · NIGMS · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Jay C. Nix · 2017 to 2026
$28.6M
GENETICS OF EUCARYOTIC AND PROCARYOTIC ORGANISMST32GM007810 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ASHRAFI, KAVEH, NARLIKAR, GEETA J · 1985 to 2020
$15.1M
Development and Testing of New Computational Methods for Ligand Discovery and MechanismR35GM122481 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Brian K Shoichet · 2017 to 2026
$8.5M
Eliminating Critical Systematic Errors In Structural Biology With Next-Generation SimulationR01GM124149 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HOLTON, JAMES M · 2017 to 2024
$2.5M
Supplement to Resolving ensemble averaged conformations by multi-temperature x-ray crystallography - Equipment 2020R01GM123159 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FRASER, JAMES SOLOMON · 2018 to 2021
$2.3M
Disentangling conformational and compositional heterogeneityF32GM133129 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI YOUNG, IRIS DIANE · 2019 to 2021
$167k
Cancer Research UK 22284NIGMS NIH HHS F32 GM133129NIGMS NIH HHS P30 GM124169NIGMS NIH HHS P30 GM133893NIGMS NIH HHS P41 GM103393NIGMS NIH HHS R01 GM123159NIGMS NIH HHS R01 GM124149NIGMS NIH HHS R35 GM122481NIGMS NIH HHS T32 GM007810Wellcome Trust
6 · The paper itself

Abstract

The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Identifiers

PMID33269349
PMCPMC7709169
OpenAlexW3110265926

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

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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.