Efficient Screening of Target-Specific Selected Compounds in Mixtures by F NMR Binding Assay with Predicted F NMR Chemical Shifts.

Ligand-based F NMR screening is a highly effective and well-established hit-finding approach. The high sensitivity to protein binding makes it particularly suitable for fragment screening. Different criteria can be considered for generating fluorinated fragment libraries. One common strategy is to assemble a large, diverse, well-designed and characterized fragment library which is screened in mixtures, generated based on experimental F NMR chemical shifts. Here, we introduce a complementary knowledge-based F NMR screening approach, named Focused screening, enabling the efficient screening of putative active molecules selected by computational hit finding methodologies, in mixtures assembled and on-the-fly deconvoluted based on predicted F NMR chemical shifts. In this study, we developed a novel approach, named LEFshift, for F NMR chemical shift prediction using rooted topological fluorine torsion fingerprints in combination with a random forest machine learning method. A demonstration of this approach to a real test case is reported.