7P2G

Identification of low micromolar SARS-CoV-2 Mpro inhibitors from hits identified by in silico screens

7P2G の概要

• エントリーDOI: 10.2210/pdb7p2g/pdb
• 分子名称: 3C-like proteinase, (4~{R})-~{N}-(4-iodophenyl)-2-oxidanylidene-3,4-dihydro-1~{H}-quinoline-4-carboxamide (3 entities in total)
• 機能のキーワード: sars-cov-2, mpro, inhibitor, protease, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34217.74

構造登録者

Rempel, S.,Halazonetis, T.D. (登録日: 2021-07-05, 公開日: 2022-05-04, 最終更新日: 2024-01-31)

主引用文献

Rossetti, G.G.,Ossorio, M.A.,Rempel, S.,Kratzel, A.,Dionellis, V.S.,Barriot, S.,Tropia, L.,Gorgulla, C.,Arthanari, H.,Thiel, V.,Mohr, P.,Gamboni, R.,Halazonetis, T.D.
Non-covalent SARS-CoV-2 M pro inhibitors developed from in silico screen hits.
Sci Rep, 12:2505-2505, 2022

PubMed Abstract: M, the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to M and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured M and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M. The most active compound from this chemotype inhibited M in vitro with an IC value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.

PubMed: 35169179
DOI: 10.1038/s41598-022-06306-4

実験手法

X-RAY DIFFRACTION (2.5 Å)