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Comprehensive and High‐Throughput Exploration of Chemical Space Using Broadband 19 F NMR‐Based Screening
Author(s) -
Lingel Andreas,
Vulpetti Anna,
Reinsperger Tony,
Proudfoot Andrew,
Denay Regis,
Frommlet Alexandra,
Henry Christelle,
Hommel Ulrich,
Gossert Alvar D.,
Luy Burkhard,
Frank Andreas O.
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202002463
Subject(s) - chemical space , broadband , robustness (evolution) , computer science , drug discovery , combinatorial chemistry , materials science , analytical chemistry (journal) , chemistry , chromatography , telecommunications , biochemistry , gene
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.