4X2K

Selection of fragments for kinase inhibitor design: decoration is key

4X2K の概要

• エントリーDOI: 10.2210/pdb4x2k/pdb
• 分子名称: TGF-beta receptor type-1, 4-[(3-aminophenyl)amino]pyrido[2,3-d]pyrimidin-5(6H)-one, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, protein kinase, inhibitor complex
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P36897
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35231.47

構造登録者

Czodrowski, P.,Hoelzemann, G.,Barnickel, G.,Greiner, H.,Musil, D. (登録日: 2014-11-26, 公開日: 2014-12-24, 最終更新日: 2024-05-08)

主引用文献

Czodrowski, P.,Holzemann, G.,Barnickel, G.,Greiner, H.,Musil, D.
Selection of fragments for kinase inhibitor design: decoration is key.
J.Med.Chem., 58:457-465, 2015

PubMed Abstract: In fragment-based screening, the choice of the best suited fragment hit among the detected hits is crucial for success. In our study, a kinase lead compound was fragmented, the hinge-binding motif extracted as a core fragment, and a minilibrary of five similar compounds with fragment-like properties was selected from our proprietary compound database. The structures of five fragments in complex with transforming growth factor β receptor type 1 kinase domain were determined by X-ray crystallography. Three different binding modes of the fragments are observed that depend on the position and the type of the substitution at the core fragment. The influence of different substituents on the preferred fragment pose was analyzed by various computational approaches. We postulate that the replacement of water molecules leads to the different binding modes.

PubMed: 25437144
DOI: 10.1021/jm501597j

実験手法

X-RAY DIFFRACTION (1.69 Å)