9NU6

SARS-CoV-2 main protease with inhibitor

This is a non-PDB format compatible entry.

Summary for 9NU6

• Entry DOI: 10.2210/pdb9nu6/pdb
• Related: 9ddf 9ddg
• Descriptor: 3C-like proteinase nsp5, N-[(3S,4S)-4-(3-chloro-5-fluorophenyl)-1-(1,6-naphthyridine-8-carbonyl)piperidin-3-yl]-N~2~-(trifluoroacetyl)-D-valinamide, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• Functional Keywords: covalent inhibitor, protease, coronavirus, antiviral, viral protein, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69082.35

Authors

Dougan, D.R. (deposition date: 2025-03-19, release date: 2025-10-22, Last modification date: 2025-11-05)

Primary citation

Okabe, A.,Carney, D.W.,Tawada, M.,Akther, T.,Aida, J.,Takagi, T.,Dougan, D.R.,Leffler, A.E.,Bell, J.A.,Frye, L.,Hickey, E.R.,Komandla, M.,Tao, W.,Selimkhanov, J.,Yonemori, K.,Chang, E.,Saikatendu, K.,Ochida, A.
Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design.
J.Med.Chem., 68:21330-21345, 2025

PubMed Abstract: The COVID-19 pandemic has highlighted a clear need to ensure rapid and equitable global access to health interventions in preparation for future coronavirus-driven pandemics. Here, we report the discovery of highly potent noncovalent inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) with pan-coronavirus (pan-CoV) Mpro inhibition through computer-aided drug design. Virtual screening led to the identification of a noncovalent hit compound with a piperazine core. Structure-guided scaffold morphing provided a novel trisubstituted piperidine core. Free energy perturbation (FEP)-guided designs, with induced-fit of Met49/Met165 and Gln189, resulted in the identification of highly potent compound , which exhibits pan-CoV Mpro inhibition and cellular antiviral efficacy against the SARS-CoV-2 omicron variant. The optimized lead compound was characterized by in vitro ADME/Tox assays and in vivo mouse pharmacokinetics. These findings suggest that compound could be an addition to the repertoire of tools used to support future pandemic preparedness.

PubMed: 41076627
DOI: 10.1021/acs.jmedchem.5c01199

Experimental method

X-RAY DIFFRACTION (2 Å)