8B56

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the inhibitor GD-9

8B56 の概要

• エントリーDOI: 10.2210/pdb8b56/pdb
• 分子名称: 3C-like proteinase nsp5, (2~{S})-4-(2-chloranylethanoyl)-1-(3,4-dichlorophenyl)-~{N}-(thiophen-2-ylmethyl)piperazine-2-carboxamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: sars-ncov, main protease, covalent inhibitor, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68695.46

構造登録者

Straeter, N.,Muller, C.E.,Claff, T.,Sylvester, K.,Weisse, R.,Gao, S.,Song, L.,Liu, X.,Zhan, P. (登録日: 2022-09-21, 公開日: 2023-08-09, 最終更新日: 2026-03-04)

主引用文献

Gao, S.,Song, L.,Claff, T.,Woodson, M.,Sylvester, K.,Jing, L.,Weisse, R.H.,Cheng, Y.,Strater, N.,Schakel, L.,Gutschow, M.,Ye, B.,Yang, M.,Zhang, T.,Kang, D.,Toth, K.,Tavis, J.,Tollefson, A.E.,Muller, C.E.,Zhan, P.,Liu, X.
Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors.
J.Med.Chem., 65:16902-16917, 2022

PubMed Abstract: The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (M) is an effective and highly conserved target for anti-SARS-CoV-2 drug design. Herein, we report the discovery of potent covalent non-peptide-derived M inhibitors. A series of covalent compounds with a piperazine scaffold containing different warheads were designed and synthesized. Among them, was identified as the most potent compound with a significant enzymatic inhibition of M (IC = 0.18 μM) and good antiviral potency against SARS-CoV-2 (EC = 2.64 μM), similar to that of remdesivir (EC = 2.27 μM). Additionally, presented favorable target selectivity for SARS-CoV-2 M versus human cysteine proteases. The X-ray co-crystal structure confirmed our original design concept showing that covalently binds to the active site of M. Our nonpeptidic covalent inhibitors provide a basis for the future development of more efficient COVID-19 therapeutics.

PubMed: 36475694
DOI: 10.1021/acs.jmedchem.2c01716

実験手法

X-RAY DIFFRACTION (1.823 Å)