7ZH8

DYRK1a in Complex with a Bromo-Triazolo-Pyridine

7ZH8 の概要

• エントリーDOI: 10.2210/pdb7zh8/pdb
• 分子名称: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, CHLORIDE ION, 6-bromanyl-3H-[1,2,3]triazolo[4,5-b]pyridine, ... (11 entities in total)
• 機能のキーワード: small molecule, kinase, halogen bond, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 185023.29

構造登録者

Dammann, M.,Stahlecker, J.,Stehle, T.,Boeckler, F.M. (登録日: 2022-04-05, 公開日: 2022-11-09, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)