Halogens are often used in rational drug design in order to improve their
ADME (absorption, distribution, metabolism, and excretion) properties. Additionally,
they are also able to establish a non-covalent interaction known as the halogen bond.
This highly directional R−X∙∙∙B interaction (X = Cl, Br or I, and B = Lewis base),
where X acts as an electrophilic species, found widespread application in several areas
such as anion recognition, supramolecular chemistry, crystal engineering, among
others. Halogen bonds were also recognized as important players in biochemical
systems, e.g. in protein-ligand recognition. Therefore, the development of
computational methodologies capable of tackling this type of interaction is of
paramount importance, in view of their application to medicinal chemistry and drug
design. Herein, we discuss the character of the halogen bond and its presence in
biomolecular systems. Afterwards, several computational methodologies are presented
and discussed, in particular, those that can be applied to large biochemical systems.
These methods range from the most computationally demanding quantum mechanics
calculations, to force field-based methods and quantitative structure–activity
relationship (QSAR) models. Selected examples where those methodologies were
applied will also be presented. Overall, this Chapter aims at providing a succinct
overview of the available computational methods to model halogen bond interactions in
biomolecular systems, and discuss the usefulness of their application in the field of
computer-aided drug design and discovery.
Keywords: ab initio, DFT, Electrostatic potential, Force field, Halogen bond,
Molecular docking, Molecular dynamics, Molecular mechanics, QSAR, σ–hole.
