Author: Schuller, Marion; Correy, Galen J.; Gahbauer, Stefan; Fearon, Daren; Wu, Taiasean; DÃaz, Roberto EfraÃn; Young, Iris D.; Martins, Luan Carvalho; Smith, Dominique H.; Schulze-Gahmen, Ursula; Owens, Tristan W.; Deshpande, Ishan; Merz, Gregory E.; Thwin, Aye C.; Biel, Justin T.; Peters, Jessica K.; Moritz, Michelle; Herrera, Nadia; Kratochvil, Huong T.; Aimon, Anthony; Bennett, James M.; Neto, Jose Brandao; Cohen, Aina E.; Dias, Alexandre; Douangamath, Alice; Dunnett, Louise; Fedorov, Oleg; Ferla, Matteo P.; Fuchs, Martin; Gorrie-Stone, Tyler J.; Holton, James M.; Johnson, Michael G.; Krojer, Tobias; Meigs, George; Powell, Ailsa J.; Rangel, Victor L; Russi, Silvia; Skyner, Rachael E.; Smith, Clyde A.; Soares, Alexei S.; Wierman, Jennifer L.; Zhu, Kang; Jura, Natalia; Ashworth, Alan; Irwin, John; Thompson, Michael C.; Gestwicki, Jason E.; von Delft, Frank; Shoichet, Brian K.; Fraser, James S.; Ahel, Ivan
Title: Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking Cord-id: 1tgtww97 Document date: 2020_11_24
ID: 1tgtww97
Snippet: 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
Document: 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.
Search related documents:
Co phrase search for related documents- active site and additional fragment: 1
- active site and adenine ribose: 1
- active site and adenosine scaffold: 1
- active site and adenosine site: 1, 2
- active site and adenosine site nucleotide: 1, 2
- active site and adp activity: 1, 2, 3, 4
- active site and adp adpr ribose: 1
- active site and adp ribose: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
- active site and adp ribose binding: 1, 2, 3
- active site and adp ribose interaction: 1
- active site and adp ribosylation: 1, 2, 3
- active site and adp ribosylation modification: 1, 2
- active site and adp ribosyltransferases: 1, 2, 3
- active site and adpr ribose: 1
- active site and loop displacement: 1
- active site and low energy: 1, 2, 3, 4, 5, 6, 7, 8
- active site and low resolution: 1, 2
- active site and low solubility: 1
- active site and mac1 active site: 1
Co phrase search for related documents, hyperlinks ordered by date