Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design

Abstract

Halogenation is an important approach in lead optimization for drug development and about half of the molecules used in high-throughput screening are halogenated. However, there is neither a suitable theoretical algorithm for evaluating the interaction between the halogen atoms of a ligand and its target protein nor a detailed understanding of how a halogen atom interacts with electron-rich atoms or groups of the residues in the binding pocket. In this Perspective, we concentrate on nonbonding interactions of halogens from both crystallographic data and theoretical viewpoints. It is found that organic halogen atoms are favorably involved in a wide variety of noncovalent protein-ligand interactions, such as halogen bonds C-X...O and hydrogen bonds C-X...H, that show remarkable differences in terms of the geometrical and energetic features. In biological molecules, heavier halogens prefer to form linear interactions with oxygen atoms and aromatic pi systems as compared to N or S, while the mean intermolecular distances for these types of halogen bonds increase with the radius or polarizability of halogen atoms, viz., Cl < Br < I. Furthermore, F...H interactions in protein-ligand complexes exhibit disparate behavior relative to X...H (X = Cl, Br, I) counterparts. These observed tendencies of the interactions involving halogens are subsequently rationalized by means of ab initio calculations using small model systems. The results presented herein should be of great use in the rational design of halogenated ligands as inhibitors and drugs as well as in biological engineering.

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

“…In view of the above, it is of interest to note that for the complexes with toluene, all calculations lead to an equilibrium structure in which the X-atom is pointing towards the ortho carbon atom C 2 , and that for none of the halogen donors studied, secondary minima on the PES could be located for the ipso, meta or para carbon atoms C 1 , C 3 or C 4 . For the complexes of toluene with CF 3 Br and CF 3 I, the geometry optimizations also lead to eclipsed orientation of the methyl group in which one hydrogen atom is situated in the plane of the aromatic ring and the other two are situated on both sides of the plane.…”

“…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].…”

In silico approach to investigating the adsorption mechanisms of short chain perfluorinated sulfonic acids and perfluorooctane sulfonic acid on hydrated hematite surface

“…3, it is natural to consider the interaction between fluorine atoms and hydrated surface caused by hydrogen bonds (HB). Subsequently, we identify the hydrogen bond formed between the F atoms of PFSA À and the O atoms of the hydrated hematite surface using the following geometric criteria to determine whether an HB was formed: d F / O 3.5 Å and 120 q O-H/F 180 (Lu et al, 2010). The HBs from 400 stable adsorbed frames during 1 ns of the simulations were counted.…”

3D-QSAR studies of triazolopyrimidine derivatives of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics, docking, and genetic algorithm-based methods

“…In recent years, the role of halogens especially fluorine in medicinal chemistry and drug design has been studied extensively [33][34][35][36], as fluorine show quite distinct qualities than other halogens due to its high electronegativity and low polarisability. According to the SAR fundamental theory, similar structures should have similar activities, but in the present dataset, compounds 10 and 14, two highly potent inhibitors, are somewhat dissimilar as also shown by their presence in two distinct clusters (Fig.…”