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.
 
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