Targeting hPKM2 in cancer: a bio isosteric approach for ligand design
Journal article
Authors | Pipitò.L, Illingworth, T.A and Deganutti.G |
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Abstract | 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. |
Keywords | hPKM2; Hypoxia; Warburg Hypothesis; Bioisosteres; Computer-aided drug design; molecular docking |
Year | 2023 |
Journal | Computers in Biology and Medicine |
Journal citation | 158, pp. 1-9 |
Publisher | Elseiver |
ISSN | 1879-0534 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.compbiomed.2023.106852 |
Web address (URL) | https://www.sciencedirect.com/science/article/pii/S0010482523003177?via%3Dihub |
Accepted author manuscript | File Access Level Open |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 07 Apr 2023 |
Publication process dates | |
Accepted | 30 Mar 2023 |
Deposited | 26 Apr 2023 |
Supplemental file | File Access Level Open |
https://repository.derby.ac.uk/item/9xy58/targeting-hpkm2-in-cancer-a-bio-isosteric-approach-for-ligand-design
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Accepted author manuscript
resubmission_hpkm2_GD_LP.docx | ||
File access level: Open |
Publisher's version
1-s2.0-S0010482523003177-main.pdf | ||
License: CC BY 4.0 | ||
File access level: Open |
Supplemental file
ADMET_Supplementary_Information.pdf | ||
File access level: Open |
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