5WBQ

Structure of human Ketohexokinase complexed with hits from fragment screening

Summary for 5WBQ

• Entry DOI: 10.2210/pdb5wbq/pdb
• Descriptor: 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)
• Functional Keywords: ketohexokinase, fragment-based drug discovery, sbdd, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69057.41

Authors

Pandit, J. (deposition date: 2017-06-29, release date: 2017-09-13, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)