8JOP

Crystal structure of the SARS-CoV-2 main protease in complex with 11a

Summary for 8JOP

• Entry DOI: 10.2210/pdb8jop/pdb
• Descriptor: 3C-like proteinase nsp5, methyl (6~{R})-5-ethanoyl-7-oxidanylidene-6-[4-(trifluoromethyl)phenyl]-8,9,10,11-tetrahydro-6~{H}-benzo[b][1,4]benzodiazepine-2-carboxylate (3 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: 1
• Total formula weight: 34283.98

Authors

Zeng, R.,Liu, Y.Z.,Wang, F.L.,Yang, S.Y.,Lei, J. (deposition date: 2023-06-08, release date: 2023-08-16, Last modification date: 2024-11-13)

Primary citation

Wang, F.,Zeng, R.,Qiao, J.,Xia, A.,Li, Y.,Li, F.,Wu, Y.,Liu, Y.,Zhao, X.,Lei, J.,Yang, S.
Discovery of benzodiazepine derivatives as a new class of covalent inhibitors of SARS-CoV-2 main protease.
Bioorg.Med.Chem.Lett., 92:129407-129407, 2023

PubMed Abstract: The COVID-19 pandemic has caused people immense suffering all over the world. Although the World Health Organization (WHO) has announced the end of the pandemic, the sporadic virus epidemic is still ongoing and may exist permanently. Effective antivirals against SARS-CoV-2 are important to deal with the long-term threat. The main protease (M) is a crucial target for drug development due to its role in the process of virus's replication and transcription. Herein, we report benzodiazepine derivatives as a new class of M inhibitors. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, methyl 10-(2-chloroacetyl)-1-oxo-11-(4-(trifluoromethyl)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepine-7-carboxylate (11a), which shows an IC value of 0.180 ± 0.004 μM. The X-ray crystal structure shows that 11a covalently binds to M. Collectively, we have obtained a new small molecule inhibitor targeting M, which can serve as a lead compound for subsequent drug discovery against SARS-CoV-2.

PubMed: 37437852
DOI: 10.1016/j.bmcl.2023.129407

Experimental method

X-RAY DIFFRACTION (2.7 Å)