Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband19F NMR-Based Screening
- 24 August 2020
- journal article
- research article
- Published by Wiley in Angewandte Chemie-International Edition
- Vol. 59 (35), 14809-14817
- https://doi.org/10.1002/anie.202002463
Abstract
Fragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous screening techniques, fluorine-detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high-quality and diverse library containing nearly 4000 fragments and screening for target-specific binders within days. At the core of the approach is a novel broadband relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like(19)F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets.Funding Information
- Deutsche Forschungsgemeinschaft (LU 835/13-1)
- Helmholtz-Gemeinschaft (BIFTM 47.02.04)
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