A Comprehensive 19F NMR Framework for Fragment-Based Drug Discovery: The Validated Screening Library OpenFL600 and Efficient Affinity Ranking by CSAR.

Abstract

Small-molecule drug discovery relies on the identification of initial chemical starting points, or screening hits, and their subsequent optimization for potency and selectivity. Fragment-based drug discovery (FBDD), particularly through 19 F NMR screening, is a powerful method for hit identification due to its high sensitivity. Here, we present the design and validation of a non-proprietary 19 F NMR screening library (OpenFL600) capable of probing diverse binding pockets, as demonstrated for RNA, G protein-coupled receptors (GPCRs), kinases, protein-protein interactions, and proteases. Our screening campaigns yielded specific hits for 11 respective targets and therefore valuable structure-activity relationship (SAR). The absence of promiscuous binders confirms the high quality of the OpenFL600 library, a result of both careful fragment selection and rigorous molecular quality control. Subsequent affinity ranking of identified hits-typically a laborious task-is considerably streamlined by fast chemical shift anisotropy (CSA) Affinity Ranking (CSAR). CSAR is enabled by providing CSA values for each fragment. This creates a highly efficient workflow, from initial hit screening to the prioritization of leads. In summary, we provide a comprehensive framework for 19 F NMR-based screening across diverse target classes, assessing their druggability, and enabling efficient affinity ranking to facilitate hit-to-lead progression.