8RJV
Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalent inhibitor GUE-3778 (compound 12 in publication)
This is a non-PDB format compatible entry.
Summary for 8RJV
| Entry DOI | 10.2210/pdb8rjv/pdb |
| Descriptor | 3C-like proteinase nsp5, (phenylmethyl) ~{N}-[(2~{S})-1-[[(3-chloranyl-2-fluoranyl-phenyl)methyl-(iminomethyl)amino]-methyl-amino]-1-oxidanylidene-3-phenyl-propan-2-yl]carbamate (3 entities in total) |
| Functional Keywords | mpro, main protease, covalent inhibitor, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus |
| Total number of polymer chains | 1 |
| Total formula weight | 34322.51 |
| Authors | Strater, N.,Claff, T.,Sylvester, K.,Mueller, C.E.,Guetschow, M.,Useini, A. (deposition date: 2023-12-21, release date: 2024-05-29, Last modification date: 2024-06-19) |
| Primary citation | Breidenbach, J.,Voget, R.,Si, Y.,Hingst, A.,Claff, T.,Sylvester, K.,Wolf, V.,Krasniqi, V.,Useini, A.,Strater, N.,Ogura, Y.,Kawaguchi, A.,Muller, C.E.,Gutschow, M. Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs. J.Med.Chem., 67:8757-8790, 2024 Cited by PubMed Abstract: Given the crucial role of the main protease (M) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M. Our systematic approach combined an M active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M inhibitor with an IC value of 3.23 nM and a second-order rate constant of inactivation, /, of 448,000 Ms. The open-chain M inhibitor , along with the macrocyclic compounds and , a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M inhibitors as anti-SARS-CoV-2 agents. PubMed: 38753594DOI: 10.1021/acs.jmedchem.4c00053 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.91 Å) |
Structure validation
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