Fluorine Interactions at the Thrombin Active Site: Protein Backbone Fragments HC_αCO Comprise a Favorable CF Environment and Interactions of CF with Electrophiles

Abstract

Abstract In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4‐fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X‐ray crystal‐structure analysis of the protein–ligand complex revealed favorable CF⋅⋅⋅HC α CO and CF⋅⋅⋅CO interactions of the 4‐F substituent of the inhibitor with the backbone HC α CO unit of Asn98. The importance of these interactions was further corroborated by the analysis of small‐molecule X‐ray crystal‐structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the C  F⋅⋅⋅CO interactions that are observed for both aromatic and aliphatic C  F units and a variety of carbonyl and carboxyl derivatives, the F atom approaches the CO C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions CF⋅⋅⋅CN, CF⋅⋅⋅CF, and CF⋅⋅⋅NO 2 , in which the F atoms interact at sub‐van der Waals distances with the electrophilic centers.

Keywords

Affiliated Institutions

• ETH Zurich CH
• Roche (Switzerland) CH

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