CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
Pyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attracti...
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Elsevier
2025-02-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025006188 |
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| author | Maia Cabrera Romina Armando Ian Czarnowski Patricio Chinestrad Ramiro Blanco Alejandra Zinni Daniel Gómez Diego L. Mengual Gómez Pablo Lorenzano Menna |
| author_facet | Maia Cabrera Romina Armando Ian Czarnowski Patricio Chinestrad Ramiro Blanco Alejandra Zinni Daniel Gómez Diego L. Mengual Gómez Pablo Lorenzano Menna |
| author_sort | Maia Cabrera |
| collection | DOAJ |
| description | Pyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attractive target for isoform-specific modulation, offering opportunities for disrupting this equilibrium and altering tumour cell dynamics.This study identifies a novel druggable pocket at the PKM2 dimer interface through conformational analysis. This pocket was exploited in a virtual screening of a large small-molecule library, identifying two promising candidates, C599 and C998. Both compounds exhibited dose-dependent antiproliferative effects in glioblastoma cell lines and induced apoptosis, as evidenced by caspase 3/7 activation. These effects were directly linked to their inhibition of PKM2 enzymatic activity, validating the proposed mechanism of action in their rational design. ADMET studies further highlighted their strong potential as lead PKM2 inhibitors for GBM treatment.Molecular dynamics (MD) simulations and post-MD analyses, including Dynamic Cross-Correlation Maps (DCCM), Probability Density Function (PDF), and Free Energy Landscape (FEL), confirmed the stability of the protein-ligand interactions and highlighted critical residues at the dimer-dimer interface. The Steered MD simulations demonstrated the high affinity of the compounds for PKM2, as evidenced by the requirement of high rupture forces to induce an unbinding event. These results highlight the potential of the compounds as oligomeric modulators of PKM2. These findings position C599 and C998 as promising lead compounds for antitumor applications. Future studies will focus on optimising these candidates and assessing their efficacy in vivo glioblastoma models, reassuring the thoroughness of our research and the potential for further advancements. |
| format | Article |
| id | doaj-art-c24971cc224d40f29ec05bdf08ed2fac |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-c24971cc224d40f29ec05bdf08ed2fac2025-01-31T05:12:04ZengElsevierHeliyon2405-84402025-02-01113e42238CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma modelsMaia Cabrera0Romina Armando1Ian Czarnowski2Patricio Chinestrad3Ramiro Blanco4Alejandra Zinni5Daniel Gómez6Diego L. Mengual Gómez7Pablo Lorenzano Menna8Laboratorio de Farmacología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Argentina; Corresponding author.Unidad de Oncología Molecular, Centro de Oncología Molecular y Traslacional, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaLaboratorio de Farmacología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaLaboratorio de Farmacología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaLaboratorio de Farmacología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaLaboratorio de Farmacología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaUnidad de Oncología Molecular, Centro de Oncología Molecular y Traslacional, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaUnidad de Oncología Molecular, Centro de Oncología Molecular y Traslacional, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaLaboratorio de Farmacología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, ArgentinaPyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attractive target for isoform-specific modulation, offering opportunities for disrupting this equilibrium and altering tumour cell dynamics.This study identifies a novel druggable pocket at the PKM2 dimer interface through conformational analysis. This pocket was exploited in a virtual screening of a large small-molecule library, identifying two promising candidates, C599 and C998. Both compounds exhibited dose-dependent antiproliferative effects in glioblastoma cell lines and induced apoptosis, as evidenced by caspase 3/7 activation. These effects were directly linked to their inhibition of PKM2 enzymatic activity, validating the proposed mechanism of action in their rational design. ADMET studies further highlighted their strong potential as lead PKM2 inhibitors for GBM treatment.Molecular dynamics (MD) simulations and post-MD analyses, including Dynamic Cross-Correlation Maps (DCCM), Probability Density Function (PDF), and Free Energy Landscape (FEL), confirmed the stability of the protein-ligand interactions and highlighted critical residues at the dimer-dimer interface. The Steered MD simulations demonstrated the high affinity of the compounds for PKM2, as evidenced by the requirement of high rupture forces to induce an unbinding event. These results highlight the potential of the compounds as oligomeric modulators of PKM2. These findings position C599 and C998 as promising lead compounds for antitumor applications. Future studies will focus on optimising these candidates and assessing their efficacy in vivo glioblastoma models, reassuring the thoroughness of our research and the potential for further advancements.http://www.sciencedirect.com/science/article/pii/S2405844025006188PKM2Pharmacological inhibitorsDocking based virtual screeningMolecular dynamics |
| spellingShingle | Maia Cabrera Romina Armando Ian Czarnowski Patricio Chinestrad Ramiro Blanco Alejandra Zinni Daniel Gómez Diego L. Mengual Gómez Pablo Lorenzano Menna CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models Heliyon PKM2 Pharmacological inhibitors Docking based virtual screening Molecular dynamics |
| title | CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models |
| title_full | CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models |
| title_fullStr | CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models |
| title_full_unstemmed | CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models |
| title_short | CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models |
| title_sort | cadd based discovery of novel oligomeric modulators of pkm2 with antitumor activity in aggressive human glioblastoma models |
| topic | PKM2 Pharmacological inhibitors Docking based virtual screening Molecular dynamics |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025006188 |
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