ArticleScience advances2021
Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.
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Article in Science advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers.
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130citing papers in PubMed
11.8field-weighted citation impact, top 1% of its field
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130 citing papers in PubMed, 202 citations in OpenAlex.
- Article
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- Synthesis and Biological Evaluation of Modified Peptide Derivatives Targeting the SARS-CoV‑2 Nsp3 Macrodomain (Mac1) Replication Domain.ACS omega · 2026Article
- Inhibiting the interaction between the mitochondrial receptor Tom70 and SARS CoV 2 Orf9b with small molecules.bioRxiv : the preprint server for biology · 2026Article
- SARS-CoV-2 nonstructural protein 3 remodels the phosphorylation of target proteins via protein-protein interactions.Microbiology spectrum · 2026Article
- Fragment-Based Development of NSP14 Exonuclease Inhibitors Confounded by Batch-to-Batch Variability.ACS chemical biology · 2026Article
- Screening assay to monitor mono-ADP-ribosylhydrolase activity of viral macrodomains in cells.Communications biology · 2026Article
- Enhancing the Outcome of Crystallographic Fragment Screening by Choosing the Optimal Protein Crystal Form.Small science · 2026Article
- Antiviral drug discovery and development: challenges and future directions.Signal transduction and targeted therapy · 2026Review
- CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2.Journal of chemical information and modeling · 2026Article
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
- Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy In Vivo.Journal of medicinal chemistry · 2026Article
- Crystal structure of fatty acid thioesterase A bound by 129 fragments provides diverse development opportunities.Pest management science · 2026Article
- Large scale prospective evaluation of co-folding across 557 Mac1-ligand complexes and three virtual screens.bioRxiv : the preprint server for biology · 2025Article
70 more citing papers are in PubMed but not listed here.
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Authors and funding
54 authors at 15 institutions in 4 countries.
Marion SchullerSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.ORCID 0000-0002-1551-0359
Galen J CorreyDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-5155-7325
Stefan GahbauerDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-3115-9757
Daren FearonDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0003-3529-7863
Taiasean WuInstitute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-6988-1414
Roberto Efraín DíazDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-1172-9919
Iris D YoungDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-4713-9504
Luan Carvalho MartinsBiochemistry Department, Institute for Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.ORCID 0000-0002-7747-6782
Dominique H SmithHelen Diller Family Comprehensive Cancer, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-5136-4491
Ursula Schulze-GahmenQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-3919-4474
Tristan W OwensQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-7423-4879
Ishan DeshpandeQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-8276-9635
Gregory E MerzQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-0842-4935
Aye C ThwinQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-1423-8189
Justin T BielQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-0935-8362
Jessica K PetersQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-3541-7431
Michelle MoritzQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-3811-5623
Nadia HerreraQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-4157-9429
Huong T KratochvilQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-8039-6823
QCRG Structural Biology Consortium
Anthony AimonDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0002-9135-129X
James M BennettCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington OX3 7DQ, UK.ORCID 0000-0003-1396-8400
Jose Brandao NetoDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0001-6015-320X
Aina E CohenStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.ORCID 0000-0003-2414-9427
Alexandre DiasDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0003-3609-7003
Alice DouangamathDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.
Louise DunnettDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0001-6710-6959
Oleg FedorovCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington OX3 7DQ, UK.ORCID 0000-0002-8662-7300
Matteo P FerlaWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.
Martin R FuchsNational Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY 11973, USA.ORCID 0000-0001-9784-0927
Tyler J Gorrie-StoneDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0002-1817-1495
James M HoltonStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.ORCID 0000-0002-0596-0137
Michael G JohnsonChemPartner Corporation, South San Francisco, CA 94080, USA.ORCID 0000-0001-9213-0598
Tobias KrojerCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington OX3 7DQ, UK.ORCID 0000-0003-0661-0814
George MeigsDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-8530-661X
Ailsa J PowellDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.ORCID 0000-0002-0462-2240
Johannes Gregor Matthias RackSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.ORCID 0000-0001-8341-6439
Victor L RangelCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington OX3 7DQ, UK.ORCID 0000-0002-7580-3452
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, UK.ORCID 0000-0003-3614-6661
Clyde A SmithStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.ORCID 0000-0002-1885-1511
Alexei S SoaresPhoton Sciences, Brookhaven National Laboratory, Upton, NY 11973, USA.ORCID 0000-0002-6565-8503
Jennifer L WiermanStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA.ORCID 0000-0002-5206-9662
Kang ZhuSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Peter O'BrienDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK.ORCID 0000-0002-9966-1962
Natalia JuraDepartment of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-5129-641X
Alan AshworthHelen Diller Family Comprehensive Cancer, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-1446-7878
John J IrwinDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-1195-6417
Michael C ThompsonDepartment of Chemistry and Biochemistry, University of California Merced, Merced, CA 95343, USA.ORCID 0000-0002-6099-2027
Jason E GestwickiDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Frank von DelftCentre for Medicines Discovery, University of Oxford, South Parks Road, Headington OX3 7DQ, UK.ORCID 0000-0003-0378-0017
Brian K ShoichetDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA. ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk.ORCID 0000-0002-6098-7367
James S FraserDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA. ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk.ORCID 0000-0002-5080-2859
Ivan AhelSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk.ORCID 0000-0002-9446-3756
QB3 · USDiamond Light Source · GBUniversity of California, San Francisco · USUniversity of Oxford · GBSLAC National Accelerator Laboratory · USBrookhaven National Laboratory · USLawrence Berkeley National Laboratory · USUCSF Helen Diller Family Comprehensive Cancer Center · USCentre for Human Genetics · GBCerner (United States) · USUniversidade de São Paulo · BRUniversidade Federal de Minas Gerais · BRUniversity of California, Merced · USUniversity of Johannesburg · ZAUniversity of York · GB
Funding
X-ray Scattering Technology CoreP30GM133893 · NIGMS · BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB · PI Vivian Stojanoff · 2019 to 2026
$38.6MX-ray Absorption Spectroscopy (XAS) pp.711-759P41GM103393 · NIGMS · STANFORD UNIVERSITY · PI HODGSON, KEITH O · 2012 to 2019
$30.6MUser Training and OutreachP30GM124169 · NIGMS · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI PAUL David ADAMS · 2017 to 2026
$28.6MRESEARCH PROJECT 2U19AI135990 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Melanie Maria Ott · 2018 to 2026
$21.4MGENETICS OF EUCARYOTIC AND PROCARYOTIC ORGANISMST32GM007810 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ASHRAFI, KAVEH, NARLIKAR, GEETA J · 1985 to 2020
$15.1MDevelopment and Testing of New Computational Methods for Ligand Discovery and MechanismR35GM122481 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Brian K Shoichet · 2017 to 2026
$8.5MA Web-Based Automatic Virtual Screening SystemR01GM071896 · NIGMS · UNIVERSITY OF TORONTO · PI IRWIN, JOHN J. · 2004 to 2024
$6.0MEliminating Critical Systematic Errors In Structural Biology With Next-Generation SimulationR01GM124149 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HOLTON, JAMES M · 2017 to 2024
$2.5MSupplement 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
$2.3MDifferential Scanning Fluorimetry (DSF) Methods for Studying Protein StabilityR01GM141299 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GESTWICKI, JASON E · 2021 to 2024
$1.5MA 600 MHz NMR console and cryoprobe for studies of macromolecules, drug discovery and cancer biomarkersS10OD023455 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GROSS, JOHN D · 2018 to 2018
$820kProton Conduction Pathways in Proton Channel ProteinsK99GM138753 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KRATOCHVIL, HUONG TRAN · 2020 to 2021
$194kCancer Research UK 22284Howard Hughes Medical InstituteNIAID NIH HHS U19 AI135990NIGMS NIH HHS F32 GM133129NIGMS NIH HHS K99 GM138753NIGMS NIH HHS P30 GM124169NIGMS NIH HHS P30 GM133893NIGMS NIH HHS P41 GM103393NIGMS NIH HHS R01 GM071896NIGMS NIH HHS R01 GM123159NIGMS NIH HHS R01 GM124149NIGMS NIH HHS R01 GM141299NIGMS NIH HHS R35 GM122481NIGMS NIH HHS T32 GM007810NIH HHS GM123159NIH HHS S10 OD023455Wellcome Trust 101794Wellcome Trust 1019894Wellcome Trust 203141/Z/16/ZWellcome Trust 210634Wellcome Trust 210634/Z/18/Z
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. 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 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 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 fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.
Indexed as
Catalytic DomainCOVID-19 Drug TreatmentCrystallography, X-RayHumansModels, MolecularMolecular Docking SimulationProtein BindingProtein ConformationSARS-CoV-2Viral Nonstructural ProteinsViral Nonstructural Proteins
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