4CIK

plasminogen kringle 1 in complex with inhibitor

4CIK の概要

• エントリーDOI: 10.2210/pdb4cik/pdb
• 分子名称: PLASMINOGEN, 5-[(2R,4S)-2-(phenylmethyl)piperidin-4-yl]-1,2-oxazol-3-one (3 entities in total)
• 機能のキーワード: hydrolase, fibrinolysis, plasminogen, protein-protein interaction, kringle ligand
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Secreted: P00747
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 9837.87

構造登録者

Xue, Y.,Johansson, C.,Cheng, L.,Pettersen, D.,Gustafsson, D. (登録日: 2013-12-10, 公開日: 2014-06-18, 最終更新日: 2024-11-06)

主引用文献

Cheng, L.,Pettersen, D.,Ohlsson, B.,Schell, P.,Karle, M.,Evertsson, E.,Pahlen, S.,Jonforsen, M.,Plowright, A.T.,Bostrom, J.,Fex, T.,Thelin, A.,Hilgendorf, C.,Xue, Y.,Wahlund, G.,Lindberg, W.,Larsson, L.,Gustafsson, D.
Discovery of the Fibrinolysis Inhibitor Azd6564, Acting Via Interference of a Protein-Protein Interaction.
Acs Med.Chem.Lett., 5:538-, 2014

PubMed Abstract: A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

PubMed: 24900876
DOI: 10.1021/ML400526D

実験手法

X-RAY DIFFRACTION (1.78 Å)