7SDC

Structure of the SARS-CoV-2 main protease in complex with inhibitor MI-09

7SDC の概要

• エントリーDOI: 10.2210/pdb7sdc/pdb
• 分子名称: 3C-like proteinase, (1R,2S,5S)-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-{[4-(trifluoromethoxy)phenoxy]acetyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• 機能のキーワード: main protease, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34281.02

構造登録者

Yang, K.S.,Liu, W.R. (登録日: 2021-09-29, 公開日: 2022-11-09, 最終更新日: 2024-11-06)

主引用文献

Geng, Z.Z.,Atla, S.,Shaabani, N.,Vulupala, V.,Yang, K.S.,Alugubelli, Y.R.,Khatua, K.,Chen, P.H.,Xiao, J.,Blankenship, L.R.,Ma, X.R.,Vatansever, E.C.,Cho, C.D.,Ma, Y.,Allen, R.,Ji, H.,Xu, S.,Liu, W.R.
A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease.
J.Med.Chem., 66:11040-11055, 2023

PubMed Abstract: SARS-CoV-2, the COVID-19 pathogen, relies on its main protease (M) for replication and pathogenesis. M is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as M inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 dipeptidyl M inhibitors and characterized them on enzymatic inhibition potency, structures of their complexes with M, cellular M inhibition potency, antiviral potency, cytotoxicity, and metabolic stability. Our results indicated that M has a flexible S2 pocket to accommodate inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as ()-2-azaspiro [4,4]nonane-3-carboxylate and ()-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics. One compound, MPI60, containing a P2 ()-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and high metabolic stability.

PubMed: 37561993
DOI: 10.1021/acs.jmedchem.3c00221

実験手法

X-RAY DIFFRACTION (1.85 Å)