5RGL

PanDDA analysis group deposition SARS-CoV-2 main protease fragment screen -- Crystal Structure of SARS-CoV-2 main protease in complex with PCM-0102962 (Mpro-x0705)

5RGL の概要

• エントリーDOI: 10.2210/pdb5rgl/pdb
• Group deposition: PanDDA analysis group deposition SARS-CoV-2 main protease fragment screen (G_1002153)
• 分子名称: 3C-like proteinase, DIMETHYL SULFOXIDE, 1-[4-(4-methylbenzene-1-carbonyl)piperazin-1-yl]ethan-1-one, ... (4 entities in total)
• 機能のキーワード: sgc - diamond i04-1 fragment screening, pandda, xchemexplorer, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34384.38

構造登録者

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. (登録日: 2020-04-07, 公開日: 2020-04-15, 最終更新日: 2021-02-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.76 Å)