7M90

CRYSTAL STRUCTURE OF THE SARS-COV-2(2019-NCOV) MAIN PROTEASE IN COMPLEX WITH COMPOUND 50

7M90 の概要

• エントリーDOI: 10.2210/pdb7m90/pdb
• 分子名称: 3C-like proteinase, 5-(3-{3-chloro-5-[2-(3-oxopiperazin-1-yl)ethoxy]phenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl)pyrimidine-2,4(1H,3H)-dione (3 entities in total)
• 機能のキーワード: viral protein, 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: 34360.50

構造登録者

Deshmukh, M.G.,Ippolito, J.A.,Zhang, C.H.,Jorgensen, W.L.,Anderson, K.S. (登録日: 2021-03-30, 公開日: 2021-06-30, 最終更新日: 2023-10-18)

主引用文献

Deshmukh, M.G.,Ippolito, J.A.,Zhang, C.H.,Stone, E.A.,Reilly, R.A.,Miller, S.J.,Jorgensen, W.L.,Anderson, K.S.
Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease.
Structure, 29:823-, 2021

PubMed Abstract: There is a clinical need for direct-acting antivirals targeting SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, to complement current therapeutic strategies. The main protease (M) is an attractive target for antiviral therapy. However, the vast majority of protease inhibitors described thus far are peptidomimetic and bind to the active-site cysteine via a covalent adduct, which is generally pharmacokinetically unfavorable. We have reported the optimization of an existing FDA-approved chemical scaffold, perampanel, to bind to and inhibit M noncovalently with ICs in the low-nanomolar range and ECs in the low-micromolar range. Here, we present nine crystal structures of M bound to a series of perampanel analogs, providing detailed structural insights into their mechanism of action and structure-activity relationship. These insights further reveal strategies for pursuing rational inhibitor design efforts in the context of considerable active-site flexibility and potential resistance mechanisms.

PubMed: 34161756
DOI: 10.1016/j.str.2021.06.002

実験手法

X-RAY DIFFRACTION (2.19 Å)