Systematic investigation of halogen bonding in protein-ligand interactions.

Halogen bonding (XB) refers to the noncovalent interaction of general structure DX···A between halogen-bearing compounds (DX: XB donor, where X=Cl, Br, I) and nucleophiles (A: XB acceptor). Since the first observation in cocrystal structures of 1,4-dioxane and Br2 by Hassel and Hvoslef in 1954, XB has been widely used in crystal engineering and solid-state supramolecular chemistry. The nature of the interaction and the underlying electronic prerequisite, the s hole in the XB donor, have been the subject of extensive theoretical studies. 7–9] Most recently, the attractive nature of XB between 1-iodoperfluoroalkanes and various donors has also been demonstrated and quantified in solution studies. Novel inhibitors of human Cathepsin L (hCatL) were discovered which bind covalently to the side chain of the catalytic Cys25 residue in the S1 pocket under formation of thioimidates, which are stabilized by the oxyanion hole of the protease. These ligands form hydrogen bonds to the backbone NH and C=O groups of Gly68 and Asp162, respectively, and fill the S2 and S3 pockets, thereby interacting with the enzyme through multiple lipophilic contacts. During the course of this research, we obtained an indication of an XB contact between a 4-chlorophenyl moiety of a ligand, whose binding affinity was enhanced by a factor of 13 compared to the unsubstituted phenyl derivative, and the backbone C=O group of Gly61 in the S3 pocket (Figure 1). This finding stimulated the prepa-