Halogen Bonding—A Novel Interaction for Rational Drug Design?

TLDR

Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. The study aims to establish halogen bonding as a potential and effective tool in drug design. The authors investigated protein–halogenated ligand complexes using a two‑layer QM/MM ONIOM approach. Halogen–oxygen contacts are shorter than van der Waals limits, comparable in strength to hydrogen bonds, follow the order H≈I>Br>Cl, and drive distinct ligand conformations in active sites, matching trends seen in small‑molecule models.

Abstract

Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. In this study, several systems of proteins in complex with halogenated ligands have been investigated by using a two-layer QM/MM ONIOM methodology. In all cases, the halogen−oxygen distances are shown to be much less than the van der Waals radius sums. Single-point energy calculations unveil that the interaction becomes comparable in magnitude to classical hydrogen bonding. Furthermore, we found that the strength of the interactions attenuates in the order H ≈ I > Br > Cl. These results agree well with the characteristics discovered within small model halogen-bonded systems. A detailed analysis of the interactions reveals that halogen bonding interactions are responsible for the different conformation of the molecules in the active site. This study would help to establish such interaction as a potential and effective tool in the context of drug design.