2R9W

AmpC beta-lactamase with bound Phthalamide inhibitor

2R9W の概要

• エントリーDOI: 10.2210/pdb2r9w/pdb
• 関連するPDBエントリー: 2PU2 2r9x
• 分子名称: Beta-lactamase, PHOSPHATE ION, 2-[(1R)-1-carboxy-2-naphthalen-1-ylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: ampc beta lactamase, pthalamide, antibiotic resistance, hydrolase
• 由来する生物種: Escherichia coli
• 細胞内の位置: Periplasm: P00811
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80904.27

構造登録者

Babaoglu, K.,Shoichet, B.K. (登録日: 2007-09-13, 公開日: 2008-04-15, 最終更新日: 2023-08-30)

主引用文献

Babaoglu, K.,Simeonov, A.,Irwin, J.J.,Nelson, M.E.,Feng, B.,Thomas, C.J.,Cancian, L.,Costi, M.P.,Maltby, D.A.,Jadhav, A.,Inglese, J.,Austin, C.P.,Shoichet, B.K.
Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase.
J.Med.Chem., 51:2502-2511, 2008

PubMed Abstract: High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against beta-lactamase using quantitative HTS (qHTS). Of the 1,274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 microM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens.

PubMed: 18333608
DOI: 10.1021/jm701500e

実験手法

X-RAY DIFFRACTION (1.8 Å)