9KSH

Crystal structure of SARS-CoV-2 main protease in complex with compound 1

これはPDB形式変換不可エントリーです。

9KSH の概要

• エントリーDOI: 10.2210/pdb9ksh/pdb
• 分子名称: 3C-like proteinase nsp5, 6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-pyridin-3-yl-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione (3 entities in total)
• 機能のキーワード: inhibitor, complex, viral protein
• 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: 33904.91

構造登録者

Zhong, Y.,Zhao, L.,Zhang, W.,Peng, W. (登録日: 2024-11-29, 公開日: 2025-04-02)

主引用文献

Yang, Q.,Huang, X.,Zhang, H.,Sun, J.,Tang, J.,Chen, Z.,Liu, L.,Liu, M.,Sun, Z.,Tang, Z.,Wei, D.,Wang, D.,Wang, Y.,Yan, M.,Zhao, L.,Zhu, A.,Zhong, Y.,Yang, H.,Zhao, Y.,Dai, J.,Shi, Y.,Huang, B.,Zhang, W.,Zhao, J.,Chen, X.,Rao, Z.,Peng, W.
Expanding the utilization of binding pockets proves to be effective for noncovalent small molecule inhibitors against SARS-CoV-2 M pro.
Eur.J.Med.Chem., 289:117497-117497, 2025

PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and continues to pose serious threats to global public health. The main protease (M) of SARS-CoV-2 is crucial for viral replication and its conservation, making it an attractive drug target. Here, we employed a structure-based drug design strategy to develop and optimize novel inhibitors targeting SARS-CoV-2 M. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC) values below 20 nM. The cocrystal structure of M with compound 10 highlighted the crucial roles of the interactions within the S3/S4 pockets in inhibitor potency enhancement. These findings demonstrated that expanding the utilization of these binding pockets was an effective strategy for developing noncovalent small molecule inhibitors that target SARS-CoV-2 M. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC of 9.4 nM. Moreover, oral treatment with compounds 1 and 9 exhibited excellent antiviral potency and substantially ameliorated virus-induced tissue damage in the lungs of Omicron BA.5-infected K18-human ACE2 (K18-hACE2) transgenic mice, indicating that these novel noncovalent inhibitors could be potential oral agents for the treatment of COVID-19.

PubMed: 40090296
DOI: 10.1016/j.ejmech.2025.117497

実験手法

X-RAY DIFFRACTION (1.91 Å)