6Y7M

Crystal structure of the complex resulting from the reaction between the SARS-CoV main protease and tert-butyl (1-((S)-3-cyclohexyl-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate

This is a non-PDB format compatible entry.

Summary for 6Y7M

• Entry DOI: 10.2210/pdb6y7m/pdb
• Descriptor: 3C-like proteinase, ~{tert}-butyl ~{N}-[1-[(2~{S})-3-cyclohexyl-1-[[(2~{S},3~{R})-4-(cyclopropylamino)-3-oxidanyl-4-oxidanylidene-1-[(3~{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]butan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-2-oxidanylidene-pyridin-3-yl]carbamate, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: coronavirus, alpha-ketoamide, antiviral, drug design, viral protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus (SARS-CoV)
• Total number of polymer chains: 1
• Total formula weight: 34540.46

Authors

Zhang, L.,Lin, D.,Hilgenfeld, R. (deposition date: 2020-03-01, release date: 2020-03-18, Last modification date: 2024-10-23)

Primary citation

Zhang, L.,Lin, D.,Sun, X.,Curth, U.,Drosten, C.,Sauerhering, L.,Becker, S.,Rox, K.,Hilgenfeld, R.
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors.
Science, 368:409-412, 2020

PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M, also called 3CL) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

PubMed: 32198291
DOI: 10.1126/science.abb3405

Experimental method

X-RAY DIFFRACTION (1.9 Å)