9FQA
Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalently bound inhibitor PSB-21101 (compound 30b in publication)
This is a non-PDB format compatible entry.
Summary for 9FQA
| Entry DOI | 10.2210/pdb9fqa/pdb |
| Descriptor | Non-structural protein 11, (5-chloranylpyridin-3-yl) 2-fluoranyl-4-phenylmethoxy-benzoate, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | protease, inhibitor, pyridyl esters, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34287.52 |
| Authors | Strater, N.,Claff, T.,Sylvester, K.,Oneto, A.,Guetschow, M.,Mueller, C.E. (deposition date: 2024-06-14, release date: 2024-08-28, Last modification date: 2024-09-25) |
| Primary citation | Oneto, A.,Hamwi, G.A.,Schakel, L.,Kruger, N.,Sylvester, K.,Petry, M.,Shamleh, R.A.,Pillaiyar, T.,Claff, T.,Schiedel, A.C.,Strater, N.,Gutschow, M.,Muller, C.E. Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity. J.Med.Chem., 67:14986-15011, 2024 Cited by PubMed Abstract: SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing a variety of substituents as irreversible inhibitors of the main viral protease (M). Altogether, 55 benzoyl chloro/bromo-pyridyl esters were synthesized, with broad variation of the substitution pattern on the benzoyl moiety. A workflow was employed for multiparametric optimization, including M inhibition assays of SARS-CoV-2 and related pathogenic coronaviruses, the duration of enzyme inhibition, the compounds' stability versus glutathione, cytotoxicity, and antiviral activity. Several compounds showed IC values in the low nanomolar range, / values of >100,000 M s and high antiviral activity. High-resolution X-ray cocrystal structures indicated an important role of -fluorobenzoyl substitution, forming a water network that stabilizes the inhibitor-bound enzyme. The most potent antiviral compound was the -ethoxy--fluorobenzoyl chloropyridyl ester (PSB-21110, , MW 296 g/mol; EC 2.68 nM), which may serve as a lead structure for broad-spectrum anticoronaviral therapeutics. PubMed: 39146284DOI: 10.1021/acs.jmedchem.4c00535 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.47 Å) |
Structure validation
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