9BBV9BBV の概要
| エントリーDOI | 10.2210/pdb9bbv/pdb |
| 分子名称 | 3C-like proteinase nsp5, N-{(1E,2R)-1-imino-3-[(3R)-2-oxopyrrolidin-3-yl]propan-2-yl}-N~2~-[4-(2-methyl-2H-indazol-4-yl)benzoyl]-L-leucinamide (3 entities in total) |
| 機能のキーワード | protease, inhibitor, viral protein, hydrolase |
| 由来する生物種 | Severe acute respiratory syndrome coronavirus 2 |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 34328.15 |
| 構造登録者 | |
| 主引用文献 | Clyde-Allen, E.,Zmudzinski, M.,Afsar, M.,James, C.,Nayak, A.,Nayak, D.,Dos Santos Bury, P.,Jochmans, D.,Neyts, J.,Scott, C.J.,Olsen, S.K.,Drag, M.,Williams, R. Identification and Exploration of a Series of SARS-Cov‐2 M Pro Cyano-Based Inhibitors Revealing Ortho-Substitution Effects within the P3 Biphenyl Group. Acs Med.Chem.Lett., 16:1935-1945, 2025 Cited by PubMed Abstract: Starting from a simple scaffold hopping exercise based on our previous exploration of cysteine protease inhibitors against legumain, compound was identified as a starting point for the development of a SARS-CoV-2 main protease (M) inhibitor. Compound displayed submicromolar biochemical potency in the ultrasensitive assay developed by Drag and co-workers. Through an iterative structure-activity relationship campaign, we discovered an unexpected improvement in both biochemical and cellular potency through the incorporation of an ortho substituent within the P3 benzamide. X-ray crystallography revealed that incorporation of the ortho substituent caused a subtle but important binding enhancement of the P1 glutamate group within the M S1 pocket. While incorporation of the ortho substituent improved the potency, the off-target selectivity against a panel of cysteine proteases and cell activity remained suboptimal. Further scanning of the P2 core revealed that incorporation of the 3.1.0 proline could address these issues and afford compound , a highly potent and cellularly active M inhibitor. PubMed: 41089474DOI: 10.1021/acsmedchemlett.5c00301 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.46 Å) |
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