9FQA

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalently bound inhibitor PSB-21101 (compound 30b in publication)

これはPDB形式変換不可エントリーです。

9FQA の概要

• エントリーDOI: 10.2210/pdb9fqa/pdb
• 分子名称: Non-structural protein 11, (5-chloranylpyridin-3-yl) 2-fluoranyl-4-phenylmethoxy-benzoate, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: protease, inhibitor, pyridyl esters, 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: 34287.52

構造登録者

Strater, N.,Claff, T.,Sylvester, K.,Oneto, A.,Guetschow, M.,Mueller, C.E. (登録日: 2024-06-14, 公開日: 2024-08-28, 最終更新日: 2024-11-20)

主引用文献

Oneto, A.,Hamwi, G.A.,Schakel, L.,Kruger, N.,Sylvester, K.,Petry, M.,Shamleh, R.A.,Pillaiyar, T.,Claff, T.,Schiedel, A.C.,Strater, N.,Gutschow, M.,Muller, C.E.
Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity.
J.Med.Chem., 67:14986-15011, 2024

PubMed Abstract: SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing a variety of substituents as irreversible inhibitors of the main viral protease (M). Altogether, 55 benzoyl chloro/bromo-pyridyl esters were synthesized, with broad variation of the substitution pattern on the benzoyl moiety. A workflow was employed for multiparametric optimization, including M inhibition assays of SARS-CoV-2 and related pathogenic coronaviruses, the duration of enzyme inhibition, the compounds' stability versus glutathione, cytotoxicity, and antiviral activity. Several compounds showed IC values in the low nanomolar range, / values of >100,000 M s and high antiviral activity. High-resolution X-ray cocrystal structures indicated an important role of -fluorobenzoyl substitution, forming a water network that stabilizes the inhibitor-bound enzyme. The most potent antiviral compound was the -ethoxy--fluorobenzoyl chloropyridyl ester (PSB-21110, , MW 296 g/mol; EC 2.68 nM), which may serve as a lead structure for broad-spectrum anticoronaviral therapeutics.

PubMed: 39146284
DOI: 10.1021/acs.jmedchem.4c00535

実験手法

X-RAY DIFFRACTION (1.47 Å)