22DR

Crystal structure of SARS-CoV-2 3CL protease in complex with compound 7c

This is a non-PDB format compatible entry.

Summary for 22DR

• Entry DOI: 10.2210/pdb22dr/pdb
• Descriptor: 3C-like proteinase, 7-[(3~{R})-3-fluoranylpyrrolidin-1-yl]-5-methoxy-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[3,4,5-tris(fluoranyl)phenyl]methyl]pyrido[4,3-d]pyrimidine-2,4-dione, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69102.39

Authors

Taoda, Y.,Hirai, K.,Sugiyama, S.,Tanaka, S.,Tomida, Y.,Akiyama, T.,Nakahara, K.,Unoh, Y.,Tachibana, Y.,Uehara, S.,Sako, Y.,Yamamoto, S.,Kawashima, S.,Nobori, H.,Kato, T. (deposition date: 2026-01-07, release date: 2026-03-25)

Primary citation

Taoda, Y.,Hirai, K.,Sugiyama, S.,Tanaka, S.,Tomida, Y.,Akiyama, T.,Nakahara, K.,Unoh, Y.,Tachibana, Y.,Uehara, S.,Sako, Y.,Yamamoto, S.,Kawashima, S.,Nobori, H.,Kato, T.
Optimization of pyridopyrimidinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors.
Bioorg.Med.Chem.Lett., 136:130619-130619, 2026

PubMed Abstract: COVID-19, an infectious disease caused by SARS-CoV-2, first identified in Wuhan, China, in 2019 and rapidly spread around the world. In response to this worldwide crisis, the research and development of antiviral drugs advanced together with vaccines, and several medications are currently being used for treatment. This study aimed to explore the structure-activity relationships (SAR) of non-covalent inhibitors of the SARS-CoV-2 3CL protease (3CL) and to develop more potent inhibitors starting from ensitrelvir, a potent non-peptide small-molecule 3CL inhibitor discovered by Shionogi & Co., Ltd. Although a previously reported dihydrofuran-ring-fused tricyclic compound 1 exhibited high antiviral activity, there were issues with its metabolic stability and solubility. Therefore, we focused on compound 2, which has a pyridopyrimidinedione scaffold, and tried to optimize its structure. Here we report compounds that have improved antiviral activity while maintaining enzyme inhibitory activity and enhanced solubility. In particular, compound 18f demonstrated a balance of potent activity, high solubility, and excellent metabolic stability. Its favorable pharmacokinetics were also confirmed in rat PK tests, suggesting that this compound offers promise as a new therapeutic agent.

PubMed: 41819156
DOI: 10.1016/j.bmcl.2026.130619

Experimental method

X-RAY DIFFRACTION (1.9 Å)