title: Fluorine local environment: from screening to drug design.
abstract: Fluorine is widely used in the lead optimization phase of drug discovery projects. More recently, fluorine NMR-based spectroscopy has emerged as a versatile, reliable and efficient tool for performing binding and biochemical assays. Different libraries of fluorinated compounds, designed by maximizing the chemical space around the fluorine atom, are screened for identifying binding fragments and for detecting putative fluorophilic hot spots on the desired macromolecular target. A statistical analysis of the fluorine NMR chemical shift, which is a marker of the fluorine local environment, and of the X-ray structures of fluorinated molecules has resulted in the development of the 'rule of shielding'. This method could become a useful tool for lead optimization and for designing novel chemical scaffolds that recognize distinct protein structural motifs.
authors.affiliation: Novartis Institutes for Biomedical Research, Global Discovery Chemistry, CADD, CH 4002 Basel, Switzerland. anna.vulpetti@novartis.com
authors.forename: Anna
authors.initials: A
authors.lastname: Vulpetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Dalvit
mesh_terms: D015195:Drug Design; D005461:Fluorine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011487:Protein Conformation; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries; D005461:Fluorine