5RG3

PanDDA analysis group deposition SARS-CoV-2 main protease fragment screen -- Crystal Structure of SARS-CoV-2 main protease in complex with NCL-00025412

Summary for 5RG3

• Entry DOI: 10.2210/pdb5rg3/pdb
• Group deposition: PanDDA analysis group deposition SARS-CoV-2 main protease fragment screen (G_1002152)
• Descriptor: 3C-like proteinase, DIMETHYL SULFOXIDE, N~2~-acetyl-N~1~-prop-2-en-1-yl-L-aspartamide, ... (4 entities in total)
• Functional Keywords: sgc - diamond i04-1 fragment screening, pandda, xchemexplorer, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 34429.45

Authors

Fearon, D.,Owen, C.D.,Douangamath, A.,Lukacik, P.,Powell, A.J.,Strain-Damerell, C.M.,Resnick, E.,Krojer, T.,Gehrtz, P.,Wild, C.,Aimon, A.,Brandao-Neto, J.,Carbery, A.,Dunnett, L.,Skyner, R.,Snee, M.,London, N.,Walsh, M.A.,von Delft, F. (deposition date: 2020-03-18, release date: 2020-04-15, Last modification date: 2024-11-06)

Primary citation

Douangamath, A.,Fearon, D.,Gehrtz, P.,Krojer, T.,Lukacik, P.,Owen, C.D.,Resnick, E.,Strain-Damerell, C.,Aimon, A.,Abranyi-Balogh, P.,Brandao-Neto, J.,Carbery, A.,Davison, G.,Dias, A.,Downes, T.D.,Dunnett, L.,Fairhead, M.,Firth, J.D.,Jones, S.P.,Keeley, A.,Keseru, G.M.,Klein, H.F.,Martin, M.P.,Noble, M.E.M.,O'Brien, P.,Powell, A.,Reddi, R.N.,Skyner, R.,Snee, M.,Waring, M.J.,Wild, C.,London, N.,von Delft, F.,Walsh, M.A.
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Nat Commun, 11:5047-5047, 2020

PubMed Abstract: COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

PubMed: 33028810
DOI: 10.1038/s41467-020-18709-w

Experimental method

X-RAY DIFFRACTION (1.58 Å)