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

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.