Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology

Abstract

Halogen bonding has been known in material science for decades, but until recently, halogen bonds in protein-ligand interactions were largely the result of serendipitous discovery rather than rational design. In this Perspective, we provide insights into the phenomenon of halogen bonding, with special focus on its role in drug discovery. We summarize the theoretical background defining its strength and directionality, provide a systematic analysis of its occurrence and interaction geometries in protein-ligand complexes, and give recent examples where halogen bonding has been successfully harnessed for lead identification and optimization. In light of these data, we discuss the potential and limitations of exploiting halogen bonds for molecular recognition and rational drug design.

Exploring the C-X…π Halogen Bonding Motif: An Infrared and Raman Study of the Complexes of CF3X (X = Cl, Br and I) with the Aromatic Model Compounds Benzene and Toluene

“…Apart from interactions where the donor atom is an oxygen, a nitrogen or a sulphur atom, an important role is assigned to the interactions of organic halogen atoms with aromatic amino acid side chains [4,5], the relative importance derived from a recent survey of protein databases being in the order of 53%, 9% and 5% for C-X···O, C-X···N and C-X···S interactions, respectively, and up to 33% for C-X···π interactions [4].…”

A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

“…Recently, the impact of halogen bonding on favorable proteinligand interactions has received increased attention, with several successful applications (49,50). In particular, fluorine and chlorine substitutions not only enhance binding affinity and specificity but also facilitate membrane permeability and metabolic stability (51,52).…”

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

“…The introduction of chlorine appeared interesting to us as it is known that this substituent, due to its σ-hole property, is able to replace classical donors like OH in H-bonding interactions. [44] On the other hand, also hydrogen bond acceptors (such as an ester or a carboxylate function) seemed promising, as it was hypothesized earlier that the OH-group of the inhibitor -as a donor -forms a hydrogen bond with the carbonyl function of the Asn152 side chain. [32] This amino acid residue, however, is in principle also able to act as an H-bond donor via its NH 2 -group, allowing for an interaction with an appropriate acceptor function of the inhibitor.…”