Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes

We conceived the
Halogen-Enriched Fragment Library (HEFLib) to
investigate the potential of halogen bonds in the early stages of
drug discovery. As the number of competitive interactions increases
with ligand size, we reasoned that a binding mode relying on halogen
bonding is more likely for fragments than highly decorated molecules.
Thus, fragments could feature unexplored binding modes. We screened
the HEFLib against the human kinase DYRK1a and verified micromolar
binding fragments via isothermal titration calorimetry (ITC). The
crystal structure of one fragment revealed a noncanonical binding
mode, despite the fragment’s classical hinge binding motif.
In addition, the fragment occupies a secondary binding site. Both
binding modes feature a halogen bond, which we evaluated by ab initio calculations. Structure–affinity relationship
(SAR) from a set of analogues improves the affinity, provides a promising
fragment-growth vector, and highlights the benefits and applicability
of halogen bonds in early lead development.