8WTI

Crystal structure of the SARS-CoV-2 main protease in complex with 20j

Summary for 8WTI

• Entry DOI: 10.2210/pdb8wti/pdb
• Descriptor: 3C-like proteinase nsp5, ~{N}-[(1~{R})-1-cyclohexyl-2-[[(2~{R})-3-methoxy-1-oxidanylidene-1-[[1-[(1~{S})-1-oxidanyl-2-oxidanylidene-2-(1,3-thiazol-2-ylmethylamino)ethyl]cyclobutyl]amino]propan-2-yl]amino]-2-oxidanylidene-ethyl]-4,4-bis(fluoranyl)cyclohexane-1-carboxamide, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: severe acute respiratory syndrome coronavirus 2, main protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69296.95

Authors

Zeng, R.,Zhao, X.,Yang, S.Y.,Lei, J. (deposition date: 2023-10-18, release date: 2024-08-28, Last modification date: 2024-11-06)

Primary citation

Huang, Q.,Quan, B.,Chen, Y.,Zhao, X.,Zhou, Y.,Huang, C.,Qiao, J.,Wang, Y.,Li, Y.,Yang, S.,Lei, J.,Li, L.
Discovery of alpha-Ketoamide inhibitors of SARS-CoV-2 main protease derived from quaternized P1 groups.
Bioorg.Chem., 143:107001-107001, 2024

PubMed Abstract: Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (M) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent α-ketoamide-containing M inhibitor, N-((R)-1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino)propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j). This compound presented promising enzymatic inhibitory activity against SARS-CoV-2 M with an IC value of 19.0 nM, and an excellent antiviral activity in cell-based assay with an EC value of 138.1 nM. This novel covalent inhibitor may be used as a lead compound for subsequent drug discovery against SARS-CoV-2.

PubMed: 38101266
DOI: 10.1016/j.bioorg.2023.107001

Experimental method

X-RAY DIFFRACTION (1.5 Å)