9BBV

SARS-CoV-2 Mpro in complex with compound 6j inhibitor

This is a non-PDB format compatible entry.

Summary for 9BBV

• Entry DOI: 10.2210/pdb9bbv/pdb
• Descriptor: 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)
• Functional Keywords: protease, inhibitor, viral protein, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34328.15

Authors

Nayak, A.,Afsar, M.,Nayak, D.,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

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: 41089474
DOI: 10.1021/acsmedchemlett.5c00301

Experimental method

X-RAY DIFFRACTION (2.46 Å)