9F3A
Crystal structure of SARS-CoV-2 Mpro in complex with RK-325
This is a non-PDB format compatible entry.
Summary for 9F3A
| Entry DOI | 10.2210/pdb9f3a/pdb |
| Descriptor | 3C-like proteinase nsp5, tert-butyl N-[1-[(2S)-3-cyclopropyl-1-[[(2S,3R)-4-(methylamino)-3-oxidanyl-4-oxidanylidene-1-[(3S)-2-oxidanylidenepyrrolidin-3-yl]butan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-5-fluoranyl-2-oxidanylidene-pyridin-3-yl]carbamate (3 entities in total) |
| Functional Keywords | complex, antiviral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 68470.00 |
| Authors | |
| Primary citation | Akula, R.K.,El Kilani, H.,Metzen, A.,Roske, J.,Zhang, K.,Gohl, M.,Arisetti, N.,Marsh, G.P.,Maple, H.J.,Cooper, M.S.,Karadogan, B.,Jochmans, D.,Neyts, J.,Rox, K.,Hilgenfeld, R.,Bronstrup, M. Structure-Based Optimization of Pyridone alpha-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease. J.Med.Chem., 2025 Cited by PubMed Abstract: The main protease M is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M inhibitors was the peptidomimetic α-ketoamide , whose cocrystal structure with M paved the way for multiple lead-finding studies. We established structure-activity relationships for the series by modifying residues at the P1', P3, and P4 sites. Guided by cocrystal structures, we reduced the P1' substituent size to better fill the pocket and added a fluorine substituent to the pyridone ring, enabling a new hydrogen bond with Gln189 in P3. Among 22 novel analogues, and inhibited M with ICs of 110 nM and 40 nM, improving the potency of by up to 9.5-fold. Compound had pronounced antiviral activity with an EC of 1.6 μM and was stable in plasma and microsomes. The study illustrates the potential of structure-based design to systematically improve peptidomimetic α-ketoamides. PubMed: 39817813DOI: 10.1021/acs.jmedchem.4c02172 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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