Vulpetti, Anna and Dalvit, Claudio (2011) Intermolecular and intramolecular hydrogen bonds involving shielded fluorine atoms: implications for recognition, selectivity and chemical properties. ChemMedChem, 7 (2). pp. 262-272. ISSN 1860-7179

Abstract

A correlation between the fluorine NMR isotropic chemical shift and close intermolecular F---H-X (with X=N or O) contacts present in the CSD X-Ray structures of fluorinated molecules is presented. An optimal F---X distance involving primary and shielded secondary fluorine atoms in hydrogen bond formation along with a correlation between F---X distance and F…H-X angle were derived. The hydrogen bonds involving fluorine are relevant not only for the recognition mechanism and for the stabilization of a preferred conformation, but also for the improvement in the permeability of the molecules, as shown with examples taken from a proprietary database. Analysis of the small number of fluorine containing natural compounds appears to strengthen the derived correlation between fluorine NMR isotropic chemical shift and interactions involving fluorine (also known as “rule of shielding”) and provides a hypothetical explanation of the recognition mechanism and catalytic activity of specific enzymes. Novel chemical scaffolds, based on the “rule of shielding”, have been designed for recognizing protein distinct structural motifs. It is envisaged that the “rule of shielding” could find useful applications in the efficient optimization of chemical fragments or promising compounds by increasing potency and selectivity against the desired biomolecular target.

Item Type:	Article
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Keywords:	Fluorine, NMR chemical shift, protein-ligand interactions, hydrogen bond, drug design, fluorine chemist, fluorinated natural compounds
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Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/6064