Nonbonding interactions of organic halogens in biological systems:
implications for drug discovery and biomolecular design

Yunxiang Lu, Yong Wang and Weiliang Zhu

Halogenation is an important approach in lead optimization for drug development and about half
of the molecules used in high-throughput screening are halogenated. However, there is neither
a suitable theoretical algorithm for evaluating the interaction between the halogen atoms
of a ligand and its target protein nor a detailed understanding of how a halogen atom interacts
with electron-rich atoms or groups of the residues in the binding pocket. In this Perspective,
we concentrate on nonbonding interactions of halogens from both crystallographic data and
theoretical viewpoints. It is found that organic halogen atoms are favorably involved in a wide
variety of noncovalent protein–ligand interactions, such as halogen bonds C–X  O and hydrogen
bonds C–X  H, that show remarkable differences in terms of the geometrical and energetic
features. In biological molecules, heavier halogens prefer to form linear interactions with oxygen
atoms and aromatic p systems as compared to N or S, while the mean intermolecular distances
for these types of halogen bonds increase with the radius or polarizability of halogen atoms, viz.,
Cl o Br o I. Furthermore, F  H interactions in protein–ligand complexes exhibit disparate
behavior relative to X  H (X = Cl, Br, I) counterparts. These observed tendencies of the
interactions involving halogens are subsequently rationalized by means of ab initio calculations
using small model systems. The results presented herein should be of great use in the rational
design of halogenated ligands as inhibitors and drugs as well as in biological engineering.