8I30

Crystal structure of the SARS-CoV-2 main protease in complex with 32j

Summary for 8I30

• Entry DOI: 10.2210/pdb8i30/pdb
• Descriptor: 3C-like proteinase nsp5, (2~{R})-1-[4,4-bis(fluoranyl)cyclohexyl]carbonyl-4,4-bis(fluoranyl)-~{N}-[(2~{R},3~{S})-3-oxidanyl-4-oxidanylidene-1-phenyl-4-(pyridin-2-ylmethylamino)butan-2-yl]pyrrolidine-2-carboxamide, CHLORIDE ION, ... (4 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: 34461.03

Authors

Zeng, R.,Huang, C.,Xie, L.W.,Wang, K.,Liu, Y.Z.,Yang, S.Y.,Lei, J. (deposition date: 2023-01-16, release date: 2023-08-16)

Primary citation

Huang, C.,Zeng, R.,Qiao, J.,Quan, B.,Luo, R.,Huang, Q.,Guo, N.,Li, Y.,Long, X.,Ma, R.,Xia, A.,Fang, Z.,Wang, Y.,Li, Y.,Zheng, Y.,Li, L.,Lei, J.,Yang, S.
Discovery and structure-activity relationship studies of novel alpha-ketoamide derivatives targeting the SARS-CoV-2 main protease.
Eur.J.Med.Chem., 259:115657-115657, 2023

PubMed Abstract: The SARS-CoV-2 main protease (M, also named 3CL) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 M inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M inhibitor (27h) with an IC value of 10.9 nM. The crystal structure of M in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for M against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 M and deserves further in-depth studies.

PubMed: 37517202
DOI: 10.1016/j.ejmech.2023.115657

Experimental method

X-RAY DIFFRACTION (2 Å)