5C27

Crystal structure of SYK in complex with compound 2

5C27 の概要

• エントリーDOI: 10.2210/pdb5c27/pdb
• 関連するPDBエントリー: 5C26
• 分子名称: Tyrosine-protein kinase SYK, GLU-VAL-TYR-GLU-SER, 3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}-N-[4-(methylcarbamoyl)phenyl]benzamide, ... (5 entities in total)
• 機能のキーワード: spleen tyrosine kinase, inhibitor, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane : P43405
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36281.20

構造登録者

Han, S.,Chang, J. (登録日: 2015-06-15, 公開日: 2015-10-07, 最終更新日: 2024-11-13)

主引用文献

Lovering, F.,Aevazelis, C.,Chang, J.,Dehnhardt, C.,Fitz, L.,Han, S.,Janz, K.,Lee, J.,Kaila, N.,McDonald, J.,Moore, W.,Moretto, A.,Papaioannou, N.,Richard, D.,Ryan, M.S.,Wan, Z.K.,Thorarensen, A.
Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free-Energy Perturbation (FEP).
Chemmedchem, 11:217-233, 2016

PubMed Abstract: There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative to the parent compound and no increase in atom count. Optimization of 17 led to compounds with nanomolar cellular activity.

PubMed: 26381330
DOI: 10.1002/cmdc.201500333

実験手法

X-RAY DIFFRACTION (2.15 Å)