title: Fluorine interactions at the thrombin active site: protein backbone fragments H-C(alpha)-C=O comprise a favorable C-F environment and interactions of C-F with electrophiles.
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(alpha)-C=O and C-F...C=O interactions of the 4-F substituent of the inhibitor with the backbone H-C(alpha)-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[triple chemical bond]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.
authors.affiliation: Laboratorium für Organische Chemie, ETH-Hönggerberg, HCI, 8093 Zürich, Switzerland.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Olsen
authors.forename: David W
authors.initials: DW
authors.lastname: Banner
authors.forename: Paul
authors.initials: P
authors.lastname: Seiler
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschopp
authors.forename: Ulrike
authors.initials: U
authors.lastname: Obst-Sander
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry*; D013237:Stereoisomerism; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D011506:Proteins; D005461:Fluorine; D010196:Pancreatic Elastase; D013917:Thrombin