9VS1

Crystal structure of SARS-CoV-2 3CL protease in complex with compound 15

This is a non-PDB format compatible entry.

Summary for 9VS1

• Entry DOI: 10.2210/pdb9vs1/pdb
• Descriptor: 3C-like proteinase, 4-chloranyl-3-[6-methyl-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-2,4,5-tris(oxidanylidene)-1-[[3,4,5-tris(fluoranyl)phenyl]methyl]pyrido[4,3-d]pyrimidin-7-yl]benzenecarbonitrile, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 69199.30

Authors

Yamamoto, S.,Taoda, Y. (deposition date: 2025-07-08, release date: 2025-09-24)

Primary citation

Taoda, Y.,Hori, A.,Tadano, G.,Sugiyama, S.,Masakado, S.,Tanaka, S.,Ogasahara, R.,Nakahara, K.,Maeno, S.,Unoh, Y.,Tachibana, Y.,Uehara, S.,Sako, Y.,Yamamoto, S.,Kawashima, S.,Nobori, H.,Kato, T.
Design, synthesis and biological evaluation of novel quinazolinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors.
Bioorg.Med.Chem.Lett., 129:130400-130400, 2025

PubMed Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has spread around the world since 2020, affecting many people and placing a heavy burden on medical facilities and the economy. The 3C-like protease (3CL) of SARS-CoV-2 is an essential enzyme for viral replication, and has been therefore attracting attention as a drug target. With the aim of creating novel non-covalent 3CL inhibitors, we planned a scaffold hopping transformation starting with ensitrelvir, which was discovered by Shionogi. Optimization of the substituents at the 5- and 7-positions of the newly designed quinazolinedione scaffold led to the discovery of compound 16, which exceeds ensitrelvir in enzyme inhibitory and antiviral activities. We solved the X-ray co-crystal structure of our synthesized inhibitor and 3CL, and clarified the interaction that contributes to its high activity. The newly discovered compound has shown good results in terms of metabolic stability and oral absorption in rat PK studies. It is expected to be a good lead compound for finding superior 3CL inhibitors.

PubMed: 40939708
DOI: 10.1016/j.bmcl.2025.130400

Experimental method

X-RAY DIFFRACTION (1.7 Å)