Halogens in Protein–Ligand Binding Mechanism: A Structural Perspective

Halogen atoms have
been at the center of many rational medicinal
chemistry applications in drug design. While fluorine and chlorine
atoms are often added to enhance physicochemical properties, bromine
and iodine elements are generally inserted to improve selectivity.
Favorable halogen interactions such as halogen bond have been thoroughly
studied through quantum mechanics and statistical analyses. Although
most of the studies focus on halogen interaction through its σ-hole,
hydrogen bonding also has a significant impact. Here, we present an
analysis describing the interacting environment of halogen atoms in
protein–ligand context. With consideration of structural redundancy
in the PDB, tendencies toward specific molecular interactions consideration
have been refined and implications for rational drug design with halogens
further discussed. Finally, we highlight the moderate occurrence of
halogen bonding and present the other roles of halogen in protein–ligand
complexes, completing the medicinal chemistry guide to rational halogen
interactions.