Targeting hPKM2 in cancer: A bio isosteric approach for ligand design

Ludovico Pipitò, Thomas Arron Illingworth, Giuseppe Deganutti

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2 Citations (Scopus)
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The term cancer refers to a plethora of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate further proximal or distal body tissues. Each type of cancer can be defined by aggressiveness, localization, metabolism, and response to available treatments. Among the most common hallmarks of cancer is a more acidic intracellular microenvironment. Offset pH values are due to an excess of lactate and an increased hypoxia-inducible factor (HIF) expression, which leads to a hypoxic state and a metabolic shift towards glycolysis to produce adenosine-5′-triphosphate (ATP) necessary for cellular metabolism. Warburg's hypothesis underpins this concept, making glycolysis and its central enzyme pyruvate kinase (hPKM2), an ideal target for drug development. Using molecular docking and extensive molecular dynamics (MD) simulations we investigated the binding mode of phosphoenolpyruvate (PEP) inside the hPKM2 active site, and then evaluated a set of known bio-isosteric inhibitors to understand the differences caused by their substitutions on their binding mode. Ultimately, we propose a new molecular entity to hamper hPKM2, unbalance cellular energy, and possibly trigger autophagic mechanisms.
Original languageEnglish
Article number106852
Number of pages9
JournalComputers in Biology and Medicine
Early online date7 Apr 2023
Publication statusPublished - May 2023

Bibliographical note

© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (


  • hPKM2
  • Hypoxia
  • Warburg hypothesis
  • Bioisosteres
  • Computer-aided drug design
  • Molecular docking


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