Advances in the Computational Modeling of Halogen Bonds in Biochemical Systems

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.