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Anthraquinone deriv...
Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase
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- Nain-Perez, Amalyn (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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- Füchtbauer, Anders (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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- Håversen, Liliana, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,Univ Gothenburg, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, SE-41345 Gothenburg, Sweden.
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- Lulla, A. (author)
- Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England.
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- Gao, Chunxia (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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- Matic, Josipa (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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- Monjas, Letitia (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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- Rodriguez, Alexandra (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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- Brear, P. (author)
- Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England.
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- Kim, Woonghee (author)
- KTH,Systembiologi,Science for Life Laboratory, SciLifeLab
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- Hyvonen, M. (author)
- Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England.
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- Borén, Jan, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,Univ Gothenburg, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, SE-41345 Gothenburg, Sweden.
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- Mardinoglu, Adil (author)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Kings Coll London, Ctr Host Micro Biome Interact, Dent Inst, London SE1 9RT, England.
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- Uhlén, Mathias (author)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi
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- Grötli, Morten (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- English.
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 234
- Related links:
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.(C) 2022 The Authors. Published by Elsevier Masson SAS.& nbsp;
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Anestesi och intensivvård (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Anesthesiology and Intensive Care (hsv//eng)
Keyword
- Liver pyruvate kinase
- ADP competitive inhibitors
- Enzymatic inhibition
- Structure-activity relationship
- Non-alcoholic fatty liver disease
- alkaloids
- isoform
- Pharmacology & Pharmacy
- Liver pyruvate kinase
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Nain-Perez, Amal ...
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Füchtbauer, Ande ...
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Håversen, Lilian ...
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Lulla, A.
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Gao, Chunxia
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Matic, Josipa
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show more...
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Monjas, Letitia
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Rodriguez, Alexa ...
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Brear, P.
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Kim, Woonghee
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Hyvonen, M.
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Borén, Jan, 1963
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Mardinoglu, Adil
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Uhlén, Mathias
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Grötli, Morten
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Gastroenterology ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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European Journal ...
- By the university
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University of Gothenburg
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Royal Institute of Technology