5WBQ

Structure of human Ketohexokinase complexed with hits from fragment screening

5WBQ の概要

• エントリーDOI: 10.2210/pdb5wbq/pdb
• 分子名称: Ketohexokinase, 2-ethyl-7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: ketohexokinase, fragment-based drug discovery, sbdd, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69057.41

構造登録者

Pandit, J. (登録日: 2017-06-29, 公開日: 2017-09-13, 最終更新日: 2023-10-04)

主引用文献

Huard, K.,Ahn, K.,Amor, P.,Beebe, D.A.,Borzilleri, K.A.,Chrunyk, B.A.,Coffey, S.B.,Cong, Y.,Conn, E.L.,Culp, J.S.,Dowling, M.S.,Gorgoglione, M.F.,Gutierrez, J.A.,Knafels, J.D.,Lachapelle, E.A.,Pandit, J.,Parris, K.D.,Perez, S.,Pfefferkorn, J.A.,Price, D.A.,Raymer, B.,Ross, T.T.,Shavnya, A.,Smith, A.C.,Subashi, T.A.,Tesz, G.J.,Thuma, B.A.,Tu, M.,Weaver, J.D.,Weng, Y.,Withka, J.M.,Xing, G.,Magee, T.V.
Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK).
J. Med. Chem., 60:7835-7849, 2017

PubMed Abstract: Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

PubMed: 28853885
DOI: 10.1021/acs.jmedchem.7b00947

実験手法

X-RAY DIFFRACTION (2.4 Å)