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Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband 19F NMR Based Screening

Lingel, Andreas, Vulpetti, Anna, Reinsperger, Tony, Proudfoot, Andrew, Denay, Regis, Frommlet, Alexandra, Gossert, Alvar, Henry, Christelle, Hommel, Ulrich, Luy, Burkhard and Frank, Andreas (2020) Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband 19F NMR Based Screening. Angewandte Chemie International Edition. ISSN 1433-78511521-3773


Fragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous available screening techniques, fluorine-detected NMR has gained immense 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 maximal compound number and minimal measurement time are required. Here, we introduce a comprehensive method that, for the first time, enables the efficient assembly of a high quality and highly diverse fragment library containing close to 4000 compounds which can be probed for specific target interactions in less than three days. At the core of the approach is a relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like 19F motifs in a single measurement. The bandwidth is achieved by employing novel broadband shaped pulses that were optimized using optimal control theory. We demonstrate that the method reliably identifies diverse, tractable binders and enables the very fast assessment of new target proteins for their ligandability.

Item Type: Article
Date Deposited: 14 Jul 2020 00:45
Last Modified: 14 Jul 2020 00:45


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