The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design

Halogen bonds (XBs) have been attracting
increasing attention in
biological systems, especially in drug discovery and design, for their
advantages of both improving drug–target binding affinity and
tuning ADME/T properties. After a comprehensive literature survey
in drug discovery and design, we found that most of the studies on
XBs between ligands and proteins have focused on the protein backbone.
Meanwhile, we also noticed that the proportion of side-chain XBs to
overall XBs decreases as structural resolution becomes lower and lower.
We postulated that protein side chains are more flexible in comparison
with backbone structures, leading to more unclear electron density
and lower resolution of the side chains. As the classic force field
used to refine protein structures from diffraction data cannot handle
XBs correctly, some of the interactions are lost during the refinement.
On the contrary, there is no change in the corresponding ratio of
hydrogen bonds (HBs) during structural resolution because HBs can
be handled well with the classic force field. Further analysis revealed
that Thr and Gln account for a large part of the decreasing XB trend,
which could be partly attributed to the misidentified N, C, or O atoms.
In addition, the lost XBs might be recovered after the atoms are reassigned,
e.g., by flipping Thr side chains. In summary, formation of XBs with
protein side chains is underestimated, and more attention should be
paid to the potential formation of XBs between organohalogens and
protein side chains during X-ray crystallography studies.