Unknown

Dataset Information

0

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.

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.

SUBMITTER: Douangamath A 

PROVIDER: S-EPMC7542442 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.

Douangamath Alice A   Fearon Daren D   Gehrtz Paul P   Krojer Tobias T   Lukacik Petra P   Owen C David CD   Resnick Efrat E   Strain-Damerell Claire C   Aimon Anthony A   Ábrányi-Balogh Péter P   Brandão-Neto José J   Carbery Anna A   Davison Gemma G   Dias Alexandre A   Downes Thomas D TD   Dunnett Louise L   Fairhead Michael M   Firth James D JD   Jones S Paul SP   Keeley Aaron A   Keserü György M GM   Klein Hanna F HF   Martin Mathew P MP   Noble Martin E M MEM   O'Brien Peter P   Powell Ailsa A   Reddi Rambabu N RN   Skyner Rachael R   Snee Matthew M   Waring Michael J MJ   Wild Conor C   London Nir N   von Delft Frank F   Walsh Martin A MA  

Nature communications 20201007 1

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 vira  ...[more]

Similar Datasets

Unknown Screening of electrophilic compounds yields an aziridinyl peptide as new active-site directed SARS-CoV main protease inhibitor.
| S-EPMC7127417 | biostudies-literature
Unknown Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket.
| S-EPMC10836397 | biostudies-literature
Unknown Galaxy workflows for fragment-based virtual screening: a case study on the SARS-CoV-2 main protease.
| S-EPMC9003163 | biostudies-literature
Unknown Biochemical screening for SARS-CoV-2 main protease inhibitors.
| S-EPMC7537881 | biostudies-literature
Unknown Fragment-based in silico design of SARS-CoV-2 main protease inhibitors.
| S-EPMC8444677 | biostudies-literature
Unknown Computational Insights into Acrylamide Fragment Inhibition of SARS-CoV-2 Main Protease.
| S-EPMC11592536 | biostudies-literature
Unknown NMR Spectroscopy of the Main Protease of SARS-CoV-2 and Fragment-Based Screening Identify Three Protein Hotspots and an Antiviral Fragment.
| S-EPMC8653025 | biostudies-literature
Unknown Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease.
| S-EPMC10250223 | biostudies-literature
Unknown Large scale peptide screening against main protease of SARS CoV-2.
| S-EPMC9877796 | biostudies-literature
Unknown Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase.
| S-EPMC8358061 | biostudies-literature