9H4B
Crystal structure of SARS-CoV-2 Mpro in complex with GK-730
This is a non-PDB format compatible entry.
Summary for 9H4B
| Entry DOI | 10.2210/pdb9h4b/pdb |
| Descriptor | 3C-like proteinase nsp5, methyl 2-[(1S,2S)-2-[[(2S)-4-methyl-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoyl]amino]-1-oxidanyl-3-[(3S)-2-oxidanylidenepyrrolidin-3-yl]propyl]-1,3-thiazole-4-carboxylate (3 entities in total) |
| Functional Keywords | protein, inhibitor, complex, antiviral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34471.31 |
| Authors | El Kilani, H.,Hilgenfeld, R. (deposition date: 2024-10-18, release date: 2025-10-29, Last modification date: 2026-08-05) |
| Primary citation | Theodoropoulou, M.A.,El Kilani, H.,Mantzourani, C.,Jochmans, D.,Neyts, J.,Zhang, K.,Roske, J.,Kokotou, M.G.,Hilgenfeld, R.,Kokotos, G. Thiazolyl 4-carboxylate ketone as a new warhead for a highly potent SARS-CoV-2 main protease inhibitor. Eur.J.Med.Chem., 303:118436-118436, 2026 Cited by PubMed Abstract: The SARS-CoV-2 main protease (M), an enzyme essential for viral replication and lacking a human homologue, has emerged as a highly attractive target for the development of novel antiviral agents. Although several M inhibitors have been developed - some receiving regulatory approval - their use is sometimes limited by drug-drug interactions. In this study, we designed and synthesized peptidomimetic SARS-CoV-2 M inhibitors incorporating a novel thiazolyl 4-carboxylate ketone warhead, previously employed by our group in the development of cytosolic phospholipase A inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory potency against SARS-CoV-2 M, and a highly potent M inhibitor (GK730) was identified (IC 5.75 nM). The melting temperature of the M-GK730 complex revealed high stability, consistent with the high inhibitory potency. The X-ray crystal structures of inhibitors GK729 and GK730 bound to M were determined, providing insights into the binding interactions and mechanism of action. Studies on the host cell proteases cathepsin B and L showed that GK730 did not inhibit cathepsin B, while exhibited weak inhibition of cathepsin L. Furthermore, GK730 demonstrated an EC value of 5.70 μM against a wild-type SARS-CoV-2 strain in Vero E6 cells and minimal cytotoxicity (CC value greater than 100 μM). PubMed: 41344111DOI: 10.1016/j.ejmech.2025.118436 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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