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Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase.

Nain-Perez A, Foller Füchtbauer A, Håversen L, Lulla A, Gao C, Matic J, Monjas L, Rodríguez A, Brear P, Kim W, Hyvönen M, Borén J, Mardinoglu A, Uhlen M, Grøtli M
Eur J Med Chem 234 114270 (2022)
Related entries: 5sc8, 5sc9, 5sca, 5scb, 5scc, 5scd, 5sce, 5scg, 5sch, 5sci, 5scj, 5sck, 5scl, 5sdt, 7qdn, 7qzu

Cited: 3 times
EuropePMC logo PMID: 35290845

Abstract

Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure-activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.

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  1. Mechanical and Physical Properties of Short Carbon Fiber and Nanofiller-Reinforced Polypropylene Hybrid Nanocomposites. Junaedi H, Baig M, Dawood A, Albahkali E, Almajid A. Polymers (Basel) 12 E2851 (2020)


Articles citing this publication (2)

  1. PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes. Swint-Kruse L, Dougherty LL, Page B, Wu T, O'Neil PT, Prasannan CB, Timmons C, Tang Q, Parente DJ, Sreenivasan S, Holyoak T, Fenton AW. Database (Oxford) 2023 baad030 (2023)
  2. Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase. Battisti UM, Monjas L, Akladios F, Matic J, Andresen E, Nagel CH, Hagkvist M, Håversen L, Kim W, Uhlen M, Borén J, Mardinoğlu A, Grøtli M. Pharmaceuticals (Basel) 16 668 (2023)


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