@article{8897cbcdfc2a418d826eeb3803fbbe8f,
title = "Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking",
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.",
author = "{QCRG Structural Biology Consortium} and Marion Schuller and Correy, {Galen J} and Stefan Gahbauer and Daren Fearon and Taiasean Wu and D{\'i}az, {Roberto Efra{\'i}n} and Young, {Iris D} and {Carvalho Martins}, Luan and Smith, {Dominique H} and Ursula Schulze-Gahmen and Owens, {Tristan W} and Ishan Deshpande and Merz, {Gregory E} and Thwin, {Aye C} and Biel, {Justin T} and Peters, {Jessica K} and Michelle Moritz and Nadia Herrera and Kratochvil, {Huong T} and Anthony Aimon and Bennett, {James M} and {Brandao Neto}, Jose and Cohen, {Aina E} and Alexandre Dias and Alice Douangamath and Louise Dunnett and Oleg Fedorov and Ferla, {Matteo P} and Fuchs, {Martin R} and Gorrie-Stone, {Tyler J} and Holton, {James M} and Johnson, {Michael G} and Tobias Krojer and George Meigs and Powell, {Ailsa J} and Rack, {Johannes Gregor Matthias} and Rangel, {Victor L} and Silvia Russi and Skyner, {Rachael E} and Smith, {Clyde A} and Soares, {Alexei S} and Wierman, {Jennifer L} and Kang Zhu and Peter O'Brien and Natalia Jura and Alan Ashworth and Irwin, {John J} and Gestwicki, {Jason E} and {von Delft}, Frank and Shoichet, {Brian K} and Fraser, {James S} and Ivan Ahel and Thompson, {Michael C}",
note = "Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",
year = "2021",
month = apr,
day = "14",
doi = "10.1126/sciadv.abf8711",
language = "English",
volume = "7",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "16",
}