7ZH8

DYRK1a in Complex with a Bromo-Triazolo-Pyridine

Summary for 7ZH8

• Entry DOI: 10.2210/pdb7zh8/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, CHLORIDE ION, 6-bromanyl-3H-[1,2,3]triazolo[4,5-b]pyridine, ... (11 entities in total)
• Functional Keywords: small molecule, kinase, halogen bond, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 185023.29

Authors

Dammann, M.,Stahlecker, J.,Stehle, T.,Boeckler, F.M. (deposition date: 2022-04-05, release date: 2022-11-09, Last modification date: 2024-10-23)

Primary citation

Dammann, M.,Stahlecker, J.,Zimmermann, M.O.,Klett, T.,Rotzinger, K.,Kramer, M.,Coles, M.,Stehle, T.,Boeckler, F.M.
Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes.
J.Med.Chem., 65:14539-14552, 2022

PubMed Abstract: 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 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.

PubMed: 36288453
DOI: 10.1021/acs.jmedchem.2c00951

Experimental method

X-RAY DIFFRACTION (2.3 Å)