9SDM
Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalently bound inhibitor GUE-4303 (compound 12 in publication)
This is a non-PDB format compatible entry.
Summary for 9SDM
| Entry DOI | 10.2210/pdb9sdm/pdb |
| Descriptor | 3C-like proteinase nsp5, N-[(2S)-1-[[(2S)-1-[2-[(3-chlorophenyl)methyl]-2-ethanoyl-hydrazinyl]-1-oxidanylidene-3-phenyl-propan-2-yl]amino]-3,3-dimethyl-1-oxidanylidene-butan-2-yl]thiophene-2-carboxamide, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | main protease, antiviral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 69203.75 |
| Authors | Yang, C.-C.,Strater, N.,Sylvester, K.,Muller, C.E.,Voget, R.,Guetschow, M. (deposition date: 2025-08-14, release date: 2026-01-14) |
| Primary citation | Voget, R.,Steiger, V.,Breidenbach, J.,Sylvester, K.,Muller-Ruttloff, C.,Yang, C.C.,Ziebuhr, J.,Strater, N.,Muller, C.E.,Gutschow, M. Sequential Optimization Approach Toward an Azapeptide-Based SARS-CoV-2 Main Protease Inhibitor. Arch Pharm, 358:e70175-e70175, 2025 Cited by PubMed Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19), is still circulating and posing a health threat to the global population. Its main protease (M) constitutes an excellent target for the development of antivirals due to its indispensable role in the viral replication cycle. In this work, we employed a sequential approach to identify a potent azapeptide-based M inhibitor. Starting from a series of small-molecule peptidomimetics, identical in their scaffold but equipped with different cysteine-reactive groups, we identified auspicious warheads. The combination of selected moieties with an optimized, previously described P1-P4 azapeptide structure resulted in a potent M inactivator (12) with a k/K value of 78,900 Ms. The chloracetohydrazide derivative 12 exhibited antiviral activity (EC = 0.47 µM), no cytotoxicity, and plasma stability. The molecular interaction of 12 with M was elucidated by an X-ray crystal structure. A thioether linkage was generated through a nucleophilic substitution of chloride by the active-site thiolate, giving rise to irreversible inhibition. PubMed: 41431928DOI: 10.1002/ardp.70175 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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