7QBB

Crystal Structure of SARS-CoV-2 main protease (Nsp5) in complex with compound 18

Summary for 7QBB

• Entry DOI: 10.2210/pdb7qbb/pdb
• Descriptor: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE, 7-isoquinolin-4-yl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34325.19

Authors

Talibov, V.O. (deposition date: 2021-11-18, release date: 2022-02-23, Last modification date: 2024-01-31)

Primary citation

Luttens, A.,Gullberg, H.,Abdurakhmanov, E.,Vo, D.D.,Akaberi, D.,Talibov, V.O.,Nekhotiaeva, N.,Vangeel, L.,De Jonghe, S.,Jochmans, D.,Krambrich, J.,Tas, A.,Lundgren, B.,Gravenfors, Y.,Craig, A.J.,Atilaw, Y.,Sandstrom, A.,Moodie, L.W.K.,Lundkvist, A.,van Hemert, M.J.,Neyts, J.,Lennerstrand, J.,Kihlberg, J.,Sandberg, K.,Danielson, U.H.,Carlsson, J.
Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses.
J.Am.Chem.Soc., 144:2905-2920, 2022

PubMed Abstract: Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.

PubMed: 35142215
DOI: 10.1021/jacs.1c08402

Experimental method

X-RAY DIFFRACTION (2 Å)