5ACV

VIM-2-OX, Discovery of novel inhibitor scaffolds against the metallo- beta-lactamase VIM-2 by SPR based fragment screening

5ACV の概要

• エントリーDOI: 10.2210/pdb5acv/pdb
• 関連するPDBエントリー: 5ACU 5ACW 5ACX
• 分子名称: BETA-LACTAMASE, HYDROXIDE ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: PSEUDOMONAS AERUGINOSA
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57239.13

構造登録者

Christopeit, T.,Carlsen, T.J.O.,Helland, R.,Leiros, H.K.S. (登録日: 2015-08-18, 公開日: 2015-11-04, 最終更新日: 2024-01-10)

主引用文献

Christopeit, T.,Carlsen, T.J.O.,Helland, R.,Leiros, H.K.S.
Discovery of Novel Inhibitor Scaffolds Against the Metallo-Beta-Lactamase Vim-2 by Spr Based Fragment Screening
J.Med.Chem., 58:8671-, 2015

PubMed Abstract: Metallo-β-lactamase (MBL) inhibitors can restore the function of carbapenem antibiotics and therefore help to treat infections of antibiotic resistant bacteria. In this study, we report novel fragments inhibiting the clinically relevant MBL Verona integron-encoded metallo-β-lactamase (VIM-2). The fragments were identified from a library of 490 fragments using an orthogonal screening approach based on a surface plasmon resonance (SPR) based assay combined with an enzyme inhibition assay. The identified fragments showed IC50 values between 14 and 1500 μM and ligand efficiencies (LE) between 0.48 and 0.23 kcal/mol per heavy atom. For two of the identified fragments, crystal structures in complex with VIM-2 were obtained. The identified fragments represent novel inhibitor scaffolds and are good starting points for the design of potent MBL inhibitors. Furthermore, the established SPR based assay and the screening approach can be adapted to other MBLs and in this way improve the drug discovery process for this important class of drug targets.

PubMed: 26477515
DOI: 10.1021/ACS.JMEDCHEM.5B01289

実験手法

X-RAY DIFFRACTION (1.963 Å)