Investigators at Roche recently published a communication describing a systematic study of halogen bonding effects in protein-ligand complexes of human Cathepsin L (hCatL). They found that an inhibitor incorporating a 4-chlorophenyl moiety enhanced binding affinity by a factor of 13, relative to the unsubstituted analogue, and x-ray cocrystal data suggested that the Cl atom made a favourable bonding interaction with a backbone CO group (see figure below). This prompted them to prepare an array of analogues designed to explore this finding more comprehensively.
Whilst this type of protein-ligand interaction is not unprecedented the study the authors describe is the first of its kind to be reported in the literature (see note below) and makes for interesting reading. The data they present, along with comparative calculated interaction energies, argue that halogen bonds in protein-ligand complexes can contribute as much to binding affinity (and binding selectivity) as is the case for hydrogen bonds. They demonstrate that the halogen bonds have strict geometrical requirements and that they increase in strength (all other factors being equal) with the mass of the halide substituent (Cl<Br<I) – with the exception of fluorides which are unable to interact in the same way. They suggest, on the basis of their results, that establishing an ideal halogen bond might enhance protein-ligand affinity by as much as 74-fold (i.e. -ΔΔG = 2.6 kcal/mol) and that targeting such interactions to enhance protein-ligand binding affinity will increasingly find utility amongst medicinal chemists.
Note: A reader recently drew our attention to an earlier publication, from a Chinese group, in which they looked at a number of halogenated ligand-protein complexes and carried out single-point energy calculations to arrive at very similar conclusions to those outlined above. They also highlighted the potential for using this type of interaction in drug design.