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.

Automated summary

This study presents the design of a Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in early stages of drug discovery. The researchers screened and verified high-affinity binding fragments against a human kinase, and discovered unexplored binding modes and the presence of halogen bonds in these fragments. The study also highlights the benefits and applicability of halogen bonds in early lead development through structure-affinity relationship analysis.