7KX5
Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with noncovalent inhibitor Jun8-76-3A
Summary for 7KX5
| Entry DOI | 10.2210/pdb7kx5/pdb |
| Descriptor | 3C-like proteinase, N-([1,1'-biphenyl]-4-yl)-N-[(1R)-2-oxo-2-{[(1S)-1-phenylethyl]amino}-1-(pyridin-3-yl)ethyl]furan-2-carboxamide, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | mpro, 76-3a, noncovalent, inhibitor, non-covalent, main protease, 3cl, sars, sars-cov-2, covid, covid-19, 3c-like, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) |
| Total number of polymer chains | 1 |
| Total formula weight | 34511.31 |
| Authors | |
| Primary citation | Ma, C.,Xia, Z.,Sacco, M.D.,Hu, Y.,Townsend, J.A.,Meng, X.,Choza, J.,Tan, H.,Jang, J.,Gongora, M.V.,Zhang, X.,Zhang, F.,Xiang, Y.,Marty, M.T.,Chen, Y.,Wang, J. Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity. J.Am.Chem.Soc., 143:20697-20709, 2021 Cited by PubMed Abstract: The main protease (M) is a validated antiviral drug target of SARS-CoV-2. A number of M inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L. In this study we describe the rational design of covalent SARS-CoV-2 M inhibitors with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, and 2-chloro-2,2-dibromoacetamide. The promising lead candidates (dichloroacetamide) and (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to , these new compounds did not inhibit the host cysteine proteases including calpain I, cathepsin B, cathepsin K, cathepsin L, and caspase-3. To the best of our knowledge, they are among the most selective covalent M inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 M with and reaffirmed our design hypothesis, showing that both compounds form a covalent adduct with the catalytic C145. Overall, these novel compounds represent valuable chemical probes for target validation and drug candidates for further development as SARS-CoV-2 antivirals. PubMed: 34860011DOI: 10.1021/jacs.1c08060 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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