Halogen Bonding on WaterA Drop in the Ocean?

Halogen bonding is a valuable interaction in drug design,
offering
an unconventional way to influence affinity and selectivity by leveraging
the halogen atoms’ ability to form directional bonds. The present
study evaluates halogen–water interactions within protein binding
sites, demonstrating that targeting a water molecule via halogen bonding
can in specific cases contribute beneficially to ligand binding. In
solving and examining the crystal structure of 2-cyclopentyl-7-iodo-1H-indole-3-carbonitrile bound to DYRK1a kinase, we identified
a notable iodine–water interaction, where water accepts a halogen
bond with good geometric and energetic features. This starting point
triggered further investigations into the prevalence of such interactions
across various halogen-bearing ligands (chlorine, bromine, iodine)
in the PDB. Using QM calculations (MP2/TZVPP), we highlight the versatility
and potential benefits of such halogen–water interactions,
particularly when the water molecule is a stable part of the binding
site’s structured environment. While the interaction energies
with water are lower compared to other typical halogen bond acceptors,
we deem this different binding strength essential for reducing desolvation
costs. We suggest that “interstitial” water molecules,
as stable parts of the binding site engaging in multiple strong interactions,
could be prime targets for halogen bonding. Further systematic studies,
combining high-resolution crystal structures and quantum chemistry,
are required to scrutinize whether halogen bonding on water is more
than a “drop in the ocean”.