9XG0

Structure of SARS-CoV-2 Mpro complexed with 4bf

This is a non-PDB format compatible entry.

Summary for 9XG0

• Entry DOI: 10.2210/pdb9xg0/pdb
• Descriptor: 3C-like proteinase nsp5, 1-[(2~{S},4~{S})-6-bromanyl-1-ethanoyl-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2~{H}-quinolin-4-yl]pyrrolidin-2-one (3 entities in total)
• Functional Keywords: protease, complex with inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34328.93

Authors

Samygina, V.R.,Vlaskina, A.V.,Namchinova, A.R. (deposition date: 2025-10-29, release date: 2026-09-23)

Primary citation

Pronina, A.A.,Shcherbakov, D.N.,Sanchez-Pimentel, A.P.,Nikitina, E.V.,Zubkov, F.I.,Meshkova, Y.V.,Marenina, M.K.,Maltsev, N.V.,Belenkaya, S.V.,Trufanov, V.O.,Volosnikova, E.A.,Zaykovskay, A.V.,Borisevich, S.S.,Khamitov, E.M.,Baev, D.S.,Mustaev, E.A.,Fedorov, A.Y.,Arkhipov, S.G.,Vlaskina, A.V.,Nemchinova, A.R.,Samygina, V.R.,Pyankov, O.V.,Yarovaya, O.,Xu, W.,Salakhutdinov, N.F.,Khvostov, M.V.
Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro.
Bioorg.Chem., 181:110402-110402, 2026

PubMed Abstract: This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf, exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.

PubMed: 42673845
DOI: 10.1016/j.bioorg.2026.110402

Experimental method

X-RAY DIFFRACTION (2.21 Å)