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

• Published in: Journal of medicinal chemistry Vol. 65; no. 21; pp. 14539 - 14552
• Main Authors: Dammann, Marcel, Stahlecker, Jason, Zimmermann, Markus O., Klett, Theresa, Rotzinger, Kilian, Kramer, Markus, Coles, Murray, Stehle, Thilo, Boeckler, Frank M.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2022; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; SIDE-CHAINS; DESIGN; ACTIVATION; INHIBITION; TRANSFER DIFFERENCE NMR; BONDS; DYRK1A; BASIS-SETS; LIGAND; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00951

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.