8Y44

Crystal structure of SARS-CoV-2 3CL protease (3CLpro) in complex with compound 44

This is a non-PDB format compatible entry.

Summary for 8Y44

• Entry DOI: 10.2210/pdb8y44/pdb
• Descriptor: 3C-like proteinase nsp5, ~{N}-[(1~{S},2~{R})-2-[(4-bromanyl-2-morpholin-4-ylcarbonyl-6-nitro-phenyl)amino]cyclohexyl]-2-oxidanylidene-1~{H}-quinoline-4-carboxamide (3 entities in total)
• Functional Keywords: mpro, viral protein-inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 68847.98

Authors

Nie, T.Q.,Su, H.X.,Li, M.J.,Xu, Y.C. (deposition date: 2024-01-30, release date: 2025-02-12, Last modification date: 2025-03-26)

Primary citation

Jiang, Z.,Feng, B.,Chen, L.,Nie, T.,Chen, S.,Wang, L.,Liu, H.,Yu, T.,Zhang, Y.,Zheng, M.,Xu, Y.,Liu, H.,Zang, Y.,Su, H.,Zhang, L.,Li, J.,Zhou, Y.
Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CL pro Inhibitors as anti-SARS-CoV-2 Drug Candidate.
J.Med.Chem., 67:12760-12783, 2024

PubMed Abstract: SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound that displayed good 3CL inhibitory activity. Here, an in-depth structural optimization for was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CL inhibitory potencies with IC values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound has the most desirable antiviral activity with EC of 0.272 ± 0.013 μM against the delta variant, which was more than 20 times stronger than . Oral administration of could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 infection.

PubMed: 39072488
DOI: 10.1021/acs.jmedchem.4c00739

Experimental method

X-RAY DIFFRACTION (1.91 Å)