9BC0
SARS-CoV-2 Mpro in complex with compound 18r inhibitor
This is a non-PDB format compatible entry.
Summary for 9BC0
| Entry DOI | 10.2210/pdb9bc0/pdb |
| Descriptor | 3C-like proteinase nsp5, 3-chloro-N-[(2R)-1-({(1Z,2S)-1-imino-3-[(3R)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4'-methoxy[1,1'-biphenyl]-4-carboxamide (3 entities in total) |
| Functional Keywords | protease, inhibitor, viral protein, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34338.57 |
| Authors | Afsar, M.,Bury, P.,Olsen, S.K. (deposition date: 2024-04-07, release date: 2025-04-16, Last modification date: 2026-04-29) |
| Primary citation | 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 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.08 Å) |
Structure validation
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