7Z0P

SARS-COV2 Main Protease in complex with inhibitor MG-131

これはPDB形式変換不可エントリーです。

7Z0P の概要

• エントリーDOI: 10.2210/pdb7z0p/pdb
• 分子名称: 3C-like proteinase nsp5, (1~{R},2~{S},5~{S})-3-[(2~{S})-2-(~{tert}-butylcarbamoylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-~{N}-[(2~{S},3~{R})-4-(methylamino)-3-oxidanyl-4-oxidanylidene-1-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]butan-2-yl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: inhibitor complex, sars-cov2, viral protein, sars-cov2 mpro
• 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: 34137.95

構造登録者

El Kilani, H.,Hilgenfeld, R. (登録日: 2022-02-23, 公開日: 2022-04-27, 最終更新日: 2024-11-20)

主引用文献

Gohl, M.,Zhang, L.,El Kilani, H.,Sun, X.,Zhang, K.,Bronstrup, M.,Hilgenfeld, R.
From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease.
Molecules, 27:-, 2022

PubMed Abstract: The main protease (M) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M. Starting from crystal structures of the M in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, , exhibited an IC of 13 nM versus the recombinant M, and similar potency was observed for its P1' -methyl derivative . Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M inhibition, we also explored the activity of against the M of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M), moderate (1.45 µM, Coxsackievirus 3C), and relatively poor (6.7 µM, enterovirus A71 3C), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus Ms but further optimization would be needed to target enterovirus 3Cs efficiently.

PubMed: 35807537
DOI: 10.3390/molecules27134292

実験手法

X-RAY DIFFRACTION (2.52 Å)