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

View ORCID ProfileMarion Schuller, View ORCID ProfileGalen J. Correy, View ORCID ProfileStefan Gahbauer, View ORCID ProfileDaren Fearon, View ORCID ProfileTaiasean Wu, View ORCID ProfileRoberto Efraín Díaz, View ORCID ProfileIris D. Young, View ORCID ProfileLuan Carvalho Martins, Dominique H. Smith, View ORCID ProfileUrsula Schulze-Gahmen, View ORCID ProfileTristan W. Owens, View ORCID ProfileIshan Deshpande, View ORCID ProfileGregory E. Merz, View ORCID ProfileAye C. Thwin, View ORCID ProfileJustin T. Biel, View ORCID ProfileJessica K. Peters, View ORCID ProfileMichelle Moritz, View ORCID ProfileNadia Herrera, View ORCID ProfileHuong T. Kratochvil, QCRG Structural Biology Consortium, View ORCID ProfileAnthony Aimon, View ORCID ProfileJames M. Bennett, View ORCID ProfileJose Brandao Neto, View ORCID ProfileAina E. Cohen, View ORCID ProfileAlexandre Dias, View ORCID ProfileAlice Douangamath, View ORCID ProfileLouise Dunnett, View ORCID ProfileOleg Fedorov, View ORCID ProfileMatteo P. Ferla, View ORCID ProfileMartin Fuchs, View ORCID ProfileTyler J. Gorrie-Stone, View ORCID ProfileJames M. Holton, Michael G. Johnson, View ORCID ProfileTobias Krojer, George Meigs, View ORCID ProfileAilsa J. Powell, View ORCID ProfileJohannes Gregor Matthias Rack, View ORCID ProfileVictor L Rangel, View ORCID ProfileSilvia Russi, View ORCID ProfileRachael E. Skyner, View ORCID ProfileClyde A. Smith, View ORCID ProfileAlexei S. Soares, View ORCID ProfileJennifer L. Wierman, View ORCID ProfileKang Zhu, View ORCID ProfileNatalia Jura, View ORCID ProfileAlan Ashworth, View ORCID ProfileJohn Irwin, View ORCID ProfileMichael C. Thompson, View ORCID ProfileJason E. Gestwicki, View ORCID ProfileFrank von Delft, View ORCID ProfileBrian K. Shoichet, View ORCID ProfileJames S. Fraser, View ORCID ProfileIvan Ahel
doi: https://doi.org/10.1101/2020.11.24.393405
Marion Schuller
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
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Galen J. Correy
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA
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Stefan Gahbauer
3Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA
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Daren Fearon
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Taiasean Wu
5Institute for Neurodegenerative Disease, University of California San Francisco, CA, USA
6Chemistry and Chemical Biology Graduate Program, University of California San Francisco, CA, USA
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Roberto Efraín Díaz
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA
7Tetrad Graduate Program, University of California San Francisco, CA, USA
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Iris D. Young
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Luan Carvalho Martins
9Biochemistry Department, Institute for Biological Sciences, Federal University of Minas Gerais. Belo Horizonte, Brazil
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Dominique H. Smith
10Helen Diller Family Comprehensive Cancer, University of California San Francisco, CA, USA
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Ursula Schulze-Gahmen
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Tristan W. Owens
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Ishan Deshpande
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Gregory E. Merz
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Aye C. Thwin
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Justin T. Biel
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Jessica K. Peters
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Michelle Moritz
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Nadia Herrera
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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Huong T. Kratochvil
8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
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8Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA
Anthony Aimon
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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James M. Bennett
11Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK
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Jose Brandao Neto
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Aina E. Cohen
12Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA
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Alexandre Dias
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Alice Douangamath
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Louise Dunnett
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Oleg Fedorov
11Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK
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Matteo P. Ferla
13Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
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Martin Fuchs
14National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY, USA
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Tyler J. Gorrie-Stone
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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James M. Holton
15Department of Biochemistry and Biophysics, University of California San Francisco, CA, USA
16Department of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
12Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA
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Michael G. Johnson
17ChemPartner Corporation, South San Francisco, CA, USA
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Tobias Krojer
11Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK
18Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK
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George Meigs
15Department of Biochemistry and Biophysics, University of California San Francisco, CA, USA
16Department of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
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Ailsa J. Powell
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Johannes Gregor Matthias Rack
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
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Victor L Rangel
11Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK
18Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK
19School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, São Paulo, Brazil
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Silvia Russi
12Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA
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Rachael E. Skyner
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
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Clyde A. Smith
12Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA
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Alexei S. Soares
20Photon Sciences, Brookhaven National Laboratory, Upton, NY, USA
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Jennifer L. Wierman
12Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA
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Kang Zhu
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
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Natalia Jura
21Department of Cellular and Molecular Pharmacology, University of California San Francisco, CA, USA
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Alan Ashworth
10Helen Diller Family Comprehensive Cancer, University of California San Francisco, CA, USA
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John Irwin
3Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA
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Michael C. Thompson
22Department of Chemistry and Chemical Biology, University of California Merced, CA, USA
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Jason E. Gestwicki
3Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA
5Institute for Neurodegenerative Disease, University of California San Francisco, CA, USA
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Frank von Delft
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom
11Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK
18Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK
23Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa
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  • For correspondence: ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk
Brian K. Shoichet
3Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA
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  • For correspondence: ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk
James S. Fraser
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA
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  • For correspondence: ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk
Ivan Ahel
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
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  • For correspondence: ivan.ahel@path.ox.ac.uk jfraser@fraserlab.com bshoichet@gmail.com frank.von-delft@diamond.ac.uk
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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.

Competing Interest Statement

N.J. is a member of the SAB of Turning Point Therapeutics and SUDO Biosciences. A.A. is a co-founder of Tango Therapeutics, Azkarra Therapeutics, Ovibio Corporation; a consultant for SPARC, Bluestar, ProLynx, Earli, Cura, GenVivo and GSK; a member of the SAB of Genentech, GLAdiator, Circle and Cambridge Science Corporation; receives grant/research support from SPARC and AstraZeneca; holds patents on the use of PARP inhibitors held jointly with AstraZeneca which he has benefitted financially (and may do so in the future). B.K.S. and J.J.I. are co-founders of a company, BlueDolphin LLC, that does fee-for-service dockingis co-founder of a company, BlueDolphin LLC, that does fee-for-service docking. J.S.F. is a founder of Keyhole Therapeutics and a shareholder of Relay Therapeutics and Keyhole Therapeutics. The Fraser laboratory has received sponsored research support from Relay Therapeutics.

Footnotes

  • ↵‡ Full listing at the end of the manuscrip

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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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, Tristan W. Owens, Ishan Deshpande, Gregory E. Merz, Aye C. Thwin, Justin T. Biel, Jessica K. Peters, Michelle Moritz, Nadia Herrera, Huong T. Kratochvil, QCRG Structural Biology Consortium, Anthony Aimon, James M. Bennett, Jose Brandao Neto, Aina E. Cohen, Alexandre Dias, Alice Douangamath, Louise Dunnett, Oleg Fedorov, Matteo P. Ferla, Martin Fuchs, Tyler J. Gorrie-Stone, James M. Holton, Michael G. Johnson, Tobias Krojer, George Meigs, Ailsa J. Powell, Johannes Gregor Matthias Rack, Victor L Rangel, Silvia Russi, Rachael E. Skyner, Clyde A. Smith, Alexei S. Soares, Jennifer L. Wierman, Kang Zhu, Natalia Jura, Alan Ashworth, John Irwin, Michael C. Thompson, Jason E. Gestwicki, Frank von Delft, Brian K. Shoichet, James S. Fraser, Ivan Ahel
bioRxiv 2020.11.24.393405; doi: https://doi.org/10.1101/2020.11.24.393405
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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, Tristan W. Owens, Ishan Deshpande, Gregory E. Merz, Aye C. Thwin, Justin T. Biel, Jessica K. Peters, Michelle Moritz, Nadia Herrera, Huong T. Kratochvil, QCRG Structural Biology Consortium, Anthony Aimon, James M. Bennett, Jose Brandao Neto, Aina E. Cohen, Alexandre Dias, Alice Douangamath, Louise Dunnett, Oleg Fedorov, Matteo P. Ferla, Martin Fuchs, Tyler J. Gorrie-Stone, James M. Holton, Michael G. Johnson, Tobias Krojer, George Meigs, Ailsa J. Powell, Johannes Gregor Matthias Rack, Victor L Rangel, Silvia Russi, Rachael E. Skyner, Clyde A. Smith, Alexei S. Soares, Jennifer L. Wierman, Kang Zhu, Natalia Jura, Alan Ashworth, John Irwin, Michael C. Thompson, Jason E. Gestwicki, Frank von Delft, Brian K. Shoichet, James S. Fraser, Ivan Ahel
bioRxiv 2020.11.24.393405; doi: https://doi.org/10.1101/2020.11.24.393405

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