7YHC

Crystal structure of VIM-2 MBL in complex with 3-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)phthalic acid

7YHC の概要

• エントリーDOI: 10.2210/pdb7yhc/pdb
• 分子名称: Beta-lactamase class B VIM-2, ZINC ION, 3-[4-(3-aminophenyl)-1,2,3-triazol-1-yl]phthalic acid, ... (4 entities in total)
• 機能のキーワード: metallo-beta-lactamase vim-2, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 201076.38

構造登録者

Li, G.-B.,Yan, Y.-H. (登録日: 2022-07-13, 公開日: 2023-06-07, 最終更新日: 2023-11-29)

主引用文献

Yan, Y.H.,Ding, H.S.,Zhu, K.R.,Mu, B.S.,Zheng, Y.,Huang, M.Y.,Zhou, C.,Li, W.F.,Wang, Z.,Wu, Y.,Li, G.B.
Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-beta-lactamase inhibitors.
Eur.J.Med.Chem., 257:115473-115473, 2023

PubMed Abstract: The emergence of metallo-β-lactamases (MBLs) confers resistance to nearly all the β-lactam antibiotics, including carbapenems. Currently, there is a lack of clinically useful MBL inhibitors, making it crucial to discover new inhibitor chemotypes that can potently target multiple clinically relevant MBLs. Herein we report a strategy that utilizes a metal binding pharmacophore (MBP) click approach to identify new broad-spectrum MBL inhibitors. Our initial investigation identified several MBPs including phthalic acid, phenylboronic acid and benzyl phosphoric acid, which were subjected to structural transformations using azide-alkyne click reactions. Subsequent structure-activity relationship analyses led to the identification of several potent broad-spectrum MBL inhibitors, including 73 that manifested IC values ranging from 0.00012 μM to 0.64 μM against multiple MBLs. Co-crystallographic studies demonstrated the importance of MBPs in engaging with the MBL active site anchor pharmacophore features, and revealed the unusual two-molecule binding modes with IMP-1, highlighting the critical role of flexible active site loops in recognizing structurally diverse substrates/inhibitors. Our work provides new chemotypes for MBL inhibition and establishes a MBP click-derived paradigm for inhibitor discovery targeting MBLs as well as other metalloenzymes.

PubMed: 37209449
DOI: 10.1016/j.ejmech.2023.115473

実験手法

X-RAY DIFFRACTION (2.153 Å)