Halogen Bonding on Water─A Drop in the Ocean?

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Halogen bonding is a key interaction in drug design, influencing ligand affinity and selectivity.
• Understanding halogen interactions with water in protein binding sites is crucial for optimizing drug candidates.

Purpose of the Study:

• To evaluate the role and prevalence of halogen-water interactions in protein binding sites.
• To investigate the potential of targeting water molecules using halogen bonding for enhanced ligand binding.

Main Methods:

• Crystal structure analysis of a ligand bound to DYRK1a kinase.
• Database screening of protein data bank (PDB) for halogen-water interactions.
• Quantum mechanics (QM) calculations (MP2/TZVPP) to assess interaction energies.

Main Results:

• Identified a significant iodine-water halogen bond in the DYRK1a kinase-ligand complex.
• Observed halogen-water interactions across various halogen types (Cl, Br, I) in the PDB.
• QM calculations confirmed the versatility and benefits of halogen-water interactions, especially with structured water molecules.

Conclusions:

• Halogen bonding with water molecules can beneficially contribute to ligand binding, particularly with stable, interstitial water.
• The moderate interaction strength with water may reduce desolvation costs, offering a unique advantage.
• Further research combining structural and computational methods is needed to fully explore this interaction's potential in drug discovery.