Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking
Category
Published on
Type
journal-article
Author
Marion Schuller and Galen J. Correy and Stefan Gahbauer and Daren Fearon and Taiasean Wu and Roberto Efraín Díaz and Iris D. Young and Luan Carvalho Martins and Dominique H. Smith and Ursula Schulze-Gahmen and Tristan W. Owens and Ishan Deshpande and Gregory E. Merz and Aye C. Thwin and Justin T. Biel and Jessica K. Peters and Michelle Moritz and Nadia Herrera and Huong T. Kratochvil and Anthony Aimon and James M. Bennett and Jose Brandao Neto and Aina E. Cohen and Alexandre Dias and Alice Douangamath and Louise Dunnett and Oleg Fedorov and Matteo P. Ferla and Martin R. Fuchs and Tyler J. Gorrie-Stone and James M. Holton and Michael G. Johnson and Tobias Krojer and George Meigs and Ailsa J. Powell and Johannes Gregor Matthias Rack and Victor L. Rangel and Silvia Russi and Rachael E. Skyner and Clyde A. Smith and Alexei S. Soares and Jennifer L. Wierman and Kang Zhu and Peter O’Brien and Natalia Jura and Alan Ashworth and John J. Irwin and Michael C. Thompson and Jason E. Gestwicki and Frank von Delft and Brian K. Shoichet and James S. Fraser and Ivan Ahel and
Citation
Schuller, M. et al., 2021. Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking. Science Advances, 7(16), p.eabf8711. Available at: http://dx.doi.org/10.1126/sciadv.abf8711.
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.
