Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking

DOI: 10.1126/sciadv.abf8711

Authors: Marion Schuller (University of Oxford) , Galen J. Correy (University of California San Francisco) , Stefan Gahbauer (University of California San Francisco) , Daren Fearon (Diamond Light Source) , Taiasean Wu (University of California San Francisco) , Roberto Efraín Díaz (University of California San Francisco) , Iris D. Young (University of California San Francisco) , Luan Carvalho Martins (Federal University of Minas Gerais) , Dominique H. Smith (University of California San Francisco) , Ursula Schulze-Gahmen (University of California San Francisco) , Tristan W. Owens (University of California San Francisco) , Ishan Deshpande (University of California San Francisco) , Gregory E. Merz (University of California San Francisco) , Aye C. Thwin (University of California San Francisco) , Justin T. Biel (University of California San Francisco) , Jessica K. Peters (University of California San Francisco) , Michelle Moritz (University of California San Francisco) , Nadia Herrera (University of California San Francisco) , Huong T. Kratochvil (University of California San Francisco) , Anthony Aimon (Diamond Light Source) , James Bennett (University of Oxford) , Jose Brandao Neto (Diamond Light Source) , Aina E. Cohen (Stanford Synchrotron Radiation Lightsource) , Alexandre Dias (Diamond Light Source) , Alice Douangamath (Diamond Light Source) , Louise Dunnett (Diamond Light Source) , Oleg Fedorov (University of Oxford) , Matteo P. Ferla (Wellcome Centre for Human Genetics, University of Oxford) , Martin R. Fuchs (National Synchrotron Light Source II) , Tyler J. Gorrie-Stone (Diamond Light Source) , James M. Holton (Stanford Synchrotron Radiation Lightsource; University of California San Francisco; Lawrence Berkeley National Laboratory) , Michael G. Johnson (ChemPartner Corporation) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , George Meigs (University of California San Francisco; Lawrence Berkeley National Laboratory) , Alisa J. Powell (Diamond Light Source) , Johannes Gregor Matthias Rack (University of Oxford) , Victor Rangel (Structural Genomics Consortium, University of Oxford; University of Sao Paulo) , Silvia Russi (Stanford Synchrotron Radiation Lightsource) , Rachael E. Skyner (Diamond Light Source; Research Complex at Harwell) , Clyde A. Smith (Stanford Synchrotron Radiation Lightsource) , Alexei S. Soares (Brookhaven National Laboratory) , Jennifer L. Wierman (Stanford Synchrotron Radiation Lightsource) , Kang Zhu (University of Oxford) , Peter O’brien (University of York) , Natalia Jura (University of California San Francisco) , Alan Ashworth (University of California San Francisco) , John J. Irwin (University of California San Francisco) , Michael C. Thompson (University of California Merced) , Jason E. Gestwicki (University of California San Francisco) , Frank Von Delft (Diamond Light Source; Structural Genomics Consortium, University of Oxford; University of Johannesburg) , Brian K. Shoichet (University of California San Francisco) , James S. Fraser (University of California San Francisco) , Ivan Ahel (University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science Advances , VOL 7

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 27001

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.

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 16/04/2021 14:00

Documents:
eabf8711.full.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening