9NWA

Crystal structure of SARS-CoV-2 main protease in complex with an inhibitor TKB-277-5Cl

This is a non-PDB format compatible entry.

Summary for 9NWA

• Entry DOI: 10.2210/pdb9nwa/pdb
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(1S,2S)-1-(5-chloro-1,3-benzothiazol-2-yl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: sars-cov-2 main protease, 3c-like proteinase, viral protein, sars-cov-2
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34497.71

Authors

Bulut, H.,Kuwata, N.,Hayashi, H.,Aoki, H.,Das, D.,Li, M.,Wlodawer, A.,Misumi, S.,Tamamura, H.,Mitsuya, H. (deposition date: 2025-03-21, release date: 2025-06-04, Last modification date: 2026-02-18)

Primary citation

Bulut, H.,Higashi-Kuwata, N.,Ogata-Aoki, H.,Hayashi, H.,Takamune, N.,Kishimoto, N.,Das, D.,Li, M.,Wlodawer, A.,Misumi, S.,Tamamura, H.,Mitsuya, H.
Impact of Single Halogen Atom Substitutions on Antiviral Profile of Inhibitors Targeting SARS-CoV‐2 Main Protease.
Acs Omega, 11:4541-4550, 2026

PubMed Abstract: The SARS-CoV-2 main protease (M) remains a prime antiviral target because its inhibition halts viral replication. To probe how subtle atomic changes influence drug performance, we carried out a systematic halogen scan on a potent ketoamide scaffold, replacing a single fluorine with chlorine, bromine, or iodine. Enzymatic assays revealed that the F- and Cl-substituted analogues inhibit M at nanomolar levels, whereas Br and I variants are 10- to 20-fold weaker. Cell-based antiviral tests mirrored this trend, yet uptake studies showed the opposite: iodine markedly enhances intracellular accumulation. High-resolution X-ray structures (1.6-1.8 Å) explain the dichotomy: small halogens fit snugly in the S1' σ-hole pocket, maximizing hydrogen-bond geometry, while bulkier atoms distort binding but create a lipophilic patch that boosts permeability. These data yield the first fluorine-to-iodine structure-activity map for SARS-CoV-2 M inhibitors. These findings highlight the critical role of halogen selection in antiviral inhibitor design.

PubMed: 41626465
DOI: 10.1021/acsomega.5c10895

Experimental method

X-RAY DIFFRACTION (1.8 Å)