7B77

Crystal Structure of SARS-CoV-2 main protease (Nsp5) in complex with compound 8

7B77 の概要

• エントリーDOI: 10.2210/pdb7b77/pdb
• 分子名称: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE, 2-(benzotriazol-1-yl)-~{N}-ethyl-~{N}-(furan-3-ylmethyl)ethanamide, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, protease, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34578.66

構造登録者

Talibov, V.O. (登録日: 2020-12-09, 公開日: 2022-02-23, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.6 Å)