8I4S

the complex structure of SARS-CoV-2 Mpro with D8

Summary for 8I4S

• Entry DOI: 10.2210/pdb8i4s/pdb
• Descriptor: ORF1a polyprotein, 3-(4-fluoranyl-3-methyl-phenyl)-2-(2-methylpropyl)-5,6,7-tris(oxidanyl)quinazolin-4-one (3 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 37461.45

Authors

Lu, M. (deposition date: 2023-01-21, release date: 2023-11-29)

Primary citation

Zhang, K.,Wang, T.,Li, M.,Liu, M.,Tang, H.,Wang, L.,Ye, K.,Yang, J.,Jiang, S.,Xiao, Y.,Xie, Y.,Lu, M.,Zhang, X.
Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M pro ).
Eur.J.Med.Chem., 257:115487-115487, 2023

PubMed Abstract: The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (M) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 M inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 M relative to baicalein (IC = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC ＞ 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 M inhibitors and anti-COVID-19 drugs.

PubMed: 37257212
DOI: 10.1016/j.ejmech.2023.115487

Experimental method

X-RAY DIFFRACTION (2.2 Å)