Halogen Bonding\non WaterA Drop in the Ocean?

Halogen bonding is a valuable interaction in drug design,\noffering\nan unconventional way to influence affinity and selectivity by leveraging\nthe halogen atoms’ ability to form directional bonds. The present\nstudy evaluates halogen–water interactions within protein binding\nsites, demonstrating that targeting a water molecule via halogen bonding\ncan in specific cases contribute beneficially to ligand binding. In\nsolving and examining the crystal structure of 2-cyclopentyl-7-iodo-1<i>H</i>-indole-3-carbonitrile bound to DYRK1a kinase, we identified\na notable iodine–water interaction, where water accepts a halogen\nbond with good geometric and energetic features. This starting point\ntriggered further investigations into the prevalence of such interactions\nacross various halogen-bearing ligands (chlorine, bromine, iodine)\nin the PDB. Using QM calculations (MP2/TZVPP), we highlight the versatility\nand potential benefits of such halogen–water interactions,\nparticularly when the water molecule is a stable part of the binding\nsite’s structured environment. While the interaction energies\nwith water are lower compared to other typical halogen bond acceptors,\nwe deem this different binding strength essential for reducing desolvation\ncosts. We suggest that “interstitial” water molecules,\nas stable parts of the binding site engaging in multiple strong interactions,\ncould be prime targets for halogen bonding. Further systematic studies,\ncombining high-resolution crystal structures and quantum chemistry,\nare required to scrutinize whether halogen bonding on water is more\nthan a “drop in the ocean”.