9F3A の概要
| エントリーDOI | 10.2210/pdb9f3a/pdb |
| 分子名称 | 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) |
| 機能のキーワード | complex, antiviral protein |
| 由来する生物種 | Severe acute respiratory syndrome coronavirus 2 |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 68470.00 |
| 構造登録者 | |
| 主引用文献 | 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 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.15 Å) |
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