Higher Contrast in 1H-Observed NMR Ligand Screening with the PEARLScreen Experiment

被引：0

作者：

Lorz, Nils ^{[1
]}

Czarniecki, Barbara ^{[2
]}

Loss, Sandra ^{[2
]}

Meier, Benno ^{[3
,4
]}

Gossert, Alvar D. ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Dept Biol, Honggerbergring 64, CH-8093 Zurich, Eswatini

[2] Bruker Switzerland AG, Ind Str 26, CH-8117 Fallanden, Switzerland

[3] Karlsruhe Inst Technol, Inst Biol Interfaces 4, Herrmann von Helmholtz Pl 1, DE-76344 Eggenstein Leopoldshafen, Germany

[4] Karlsruhe Inst Technol, Inst Phys Chem, Fritz Haber Weg 2, DE-76131 Karlsruhe, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2025年

基金：

欧洲研究理事会;

关键词：

NMR spectroscopy; drug screening; PEARLScreen; perfect echo; fragment-based drug discovery; DRUG DISCOVERY; BINDING; IDENTIFICATION; ADENYLYLTRANSFERASE; RELAXATION; MOLECULES; AFFINITY; TRYPSIN; IMPACT; TARGET;

D O I：

10.1002/anie.202423879

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

For initial hit identification in fragment-based drug design, NMR is one of the preferred methods, with the well-established ligand screening experiments T1 rho, waterLOGSY and STD. Here, we present a new, perfect echo-based experiment with superior binding sensitivity, the PEARLScreen. The sensitivity enhancement is based on longer relaxation delays as well as active exchange broadening, enabled by the perfect echo scheme. This allowed a reduction of the protein concentration by up to one order of magnitude in comparison to the conventional experiments on the same screening setup without losing binding sensitivity. The experiment was tested throughout the whole field range of commercially available spectrometers from 80 to 1200 MHz, where at the highest field even a reduction of the required protein amount by a factor of 40 is within reach, thanks to larger compound mixtures and enhanced exchange effects. Based on the superior performance already on standard NMR setups, we expect the PEARLScreen to become the standard screening experiment for 1H-detected ligand screening.

引用

页数：11