Halogen Interactions in Protein–Ligand Complexes: Implications of Halogen Bonding for Rational Drug Design

Abstract

Halogen bonding interactions between halogenated ligands and proteins were examined using the crystal structures deposited to date in the PDB. The data was analyzed as a function of halogen bonding to main chain Lewis bases, viz. oxygen of backbone carbonyl and backbone amide nitrogen. This analysis also examined halogen bonding to side-chain Lewis bases (O, N, and S) and to the electron-rich aromatic amino acids. All interactions were restricted to van der Waals radii with respective atoms. The data reveals that while fluorine and chlorine have strong tendencies favoring interactions with the backbone Lewis bases at glycine, the trend is not restricted to the achiral amino acid backbone for larger halogens. Halogen side-chain interactions are not restricted to amino acids containing O, N, and S as Lewis bases. Electron-rich aromatic amino acids host a high frequency of halogen bonds as does Leu. A closer examination of the latter hydrophobic side chain reveals that the "propensity of interactions" of halogen ligands at this oily residue is an outcome of strong classical halogen bonds with Lewis bases in the vicinity. Finally, an examination of Θ1 (C-X···O and C-X···N) and Θ2 (X···O-Z and X···N-Z) angles reveals that very few ligands adopt classical halogen bonding angles, suggesting that steric and other factors may influence these angles. The data is discussed in the context of ligand design for pharmaceutical applications.

Insights into halogen bond-driven enantioseparations

“…2B). The carbonyl-halogen bonds have been widely studied in medicinal chemistry, which showed to have a relevant role in protein-pharmacophore complexes [24,25]. In nature, halogenated XB donors are not unusual and the selective binding of the hormone thyroxine (T4) to its transporter protein transthyretin involves iodine-carbonyl oxygen interaction, for instance [26].…”

6-Chloro-4-oxo-4H-chromene-3-carbaldehyde

“…For van der Waals radii; see: Bondi (1964). For halogen bonding, see: Auffinger et al (2004);Metrangolo et al (2005); Sirimulla et al (2013).…”

“…Halogen bonds have been found to occur in organic, inorganic and biological systems, and have recently attracted much attention in medicinal chemistry, chemical biology and supramolecular chemistry (Auffinger et al, 2004;Metrangolo et al, 2005;Sirimulla et al, 2013). We have recently reported the crystal structures of dihalogenated 3-formylchromone derivatives 6,8-dichloro-4-oxochromene-3-carbaldehyde (Ishikawa & Motohashi, 2013;Fig.…”

8-Fluoro-4-oxo-4H-chromene-3-carbaldehyde

“…For the synthesis of the precursor of the title compound, see: Valoti et al (2001). For halogen bonding, see: Auffinger et al (2004); Metrangolo et al (2005); Wilcken et al (2013); Sirimulla et al (2013). Table 1 Hydrogen-bond geometry (Å , ).…”