Introduction: Halogens have a prominent role in drug design. Often used as a mean to improve ADME properties, they are also becoming a tool in protein-ligand recognition given their ability to form a non-covalent interaction, termed halogen bond, where halogens act as electrophilic species interacting with electron-rich partners. Rational drug design of halogen-bonding lead molecules requires an accurate description of halocarbon-protein complexes by computational tools though not all methods are able to tackle this non-covalent interaction. Areas covered: The authors present a review of computational methodologies that can be used to properly describe halogen bonds in the context of protein-ligand complexes, providing also insights on how these methods can be used in the context of computer-aided drug design. Expert opinion: Although in the last few years many computational tools, ranging from fast screening methods to the more expensive QM calculations, have been developed to tackle the halogen bonding phenomenon, they are not yet standard in the literature. This will eventually change as official software distributions are including support for halogen bonding in their methods. Tackling desolvation of halogenated species seems to be a good strategy to improve the accuracy of computational methods, that will be more commonly used prior to laboratory work in the future.
Keywords: Halogen bonding; drug design; force field; molecular docking; protein-ligand complexes; quantum-mechanical calculations; σ-hole.