Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Letters in Drug Design & Discovery
  4. Volume 21, Issue 13
  5. Article
Volume 21, Issue 13
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

The prevalence of cancer in developing nations is a significant issue of concern. As a result of diverse global influences, this condition has surpassed coronary ailments to become the foremost cause of mortality. The role of PKM2 (Muscle Pyruvate Kinase 2) has garnered significant interest in the quest for agents in cancer progression. Flavonoids exhibit promise as a framework for the advancement of chemotherapeutic agents targeting cancer.

Objective

The principal aim of the present investigation was to ascertain flavonoids as potential anticancer agents capable of inhibiting the PKM2 enzyme.

Methods

The preferred ligand molecules were docked to the human PKM2 enzyme using a computational molecular docking simulation technique to determine their affinity for the same enzyme. The molecular docking simulation was carried out using the AutoDock Vina software.

Results

The chosen flavonoid docked well with the PKM2 enzyme, suggesting it may stimulate autophagy, hence acting as an anticancer agent.

Conclusion

In studies, the chosen flavonoids showed a strong binding affinity, indicating that all of them impede the human PKM2 enzyme and have the potential to be used as cancer treatment alternatives.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/1570180820666230816090541
2023-12-12
2025-06-21

  • From This Site

    /content/journals/lddd/10.2174/1570180820666230816090541
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. HaiderK. ShafeequeM. YahyaS. YarM.S. A comprehensive review on pyrazoline based heterocyclic hybrids as potent anticancer agents.Eur. J. Med. Chem. Reports2022510004210004210.1016/j.ejmcr.2022.100042
     [Google Scholar]
  2. SarkarR. BanerjeeS. AminS.A. AdhikariN. JhaT. Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review.Eur. J. Med. Chem.202019211217111217110.1016/j.ejmech.2020.112171 32163814
     [Google Scholar]
  3. HarwanshR.K. DeshmukhR. Breast cancer: An insight into its inflammatory, molecular, pathological and targeted facets with update on investigational drugs.Crit. Rev. Oncol. Hematol.202015410307010307010.1016/j.critrevonc.2020.103070 32871325
     [Google Scholar]
  4. ShahK. ChhabraS. Singh ChauhanN. Chemistry and anticancer activity of cardiac glycosides: A review.Chem. Biol. Drug Des.2022100336437510.1111/cbdd.14096 35638893
     [Google Scholar]
  5. MishraR. KumarN. SachanN. Synthesis, biological evaluation, and docking analysis of novel tetrahydrobenzothiophene derivatives.Lett. Drug Des. Discov.202219653054010.2174/1570180819666220117123958
     [Google Scholar]
  6. MishraR. KumarN. SachanN. Synthesis, pharmacological evaluation, and in-silico studies of thiophene derivatives.Oncologie202123449351410.32604/oncologie.2021.018532
     [Google Scholar]
  7. MishraR. KumarN. MishraI. SachanN. A review on anticancer activities of thiophene and its analogs.Mini Rev. Med. Chem.202020191944196510.2174/1389557520666200715104555 32669077
     [Google Scholar]
  8. KaratiD. KumarD. Exploring the structural and functional requirements of Phyto-compounds and their synthetic scaffolds as anticancer agents: Medicinal chemistry perspective.Pharmacol. Res. - Modern Chinese Med.2022410012310012310.1016/j.prmcm.2022.100123
     [Google Scholar]
  9. GodmanC.A. JoshiR. TierneyB.R. GreenspanE. RasmussenT.P. WangH. ShinD.G. RosenbergD.W. GiardinaC. HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling.Cancer Biol. Ther.20087101570158010.4161/cbt.7.10.6561 18769117
     [Google Scholar]
  10. SmeltzerS. C. BareB. G. HinkleJ. L. CheeverK. H. PandeyG. MadhuriS. Brunner and Suddarth’s Textbook of Medical Surgical NursingLippincott Williams & WIlkins2010
     [Google Scholar]
  11. MousaviS.M. GouyaM.M. RamazaniR. DavanlouM. HajsadeghiN. SeddighiZ. Cancer incidence and mortality in Iran.Ann. Oncol.200920355656310.1093/annonc/mdn642 19073863
     [Google Scholar]
  12. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality Worldwide for 36 Cancers in 185 Countries.CA Cancer J. Clin.202171320924910.3322/caac.21660 33538338
     [Google Scholar]
  13. FerlayJ. ColombetM. SoerjomataramI. Global and regional estimates of the incidence and mortality for 38 cancers: GLOBOCAN. International Agency for Research on Cancer/ World.,2018
     [Google Scholar]
  14. AlmouhannaF. BlagojevicB. CanS. GhanemA. WölflS. Pharmacological activation of pyruvate kinase M2 reprograms glycolysis leading to TXNIP depletion and AMPK activation in breast cancer cells.Cancer Metab.202191510.1186/s40170‑021‑00239‑8 33482908
     [Google Scholar]
  15. HsuP.P. SabatiniD.M. Cancer cell metabolism: Warburg and beyond.Cell2008134570370710.1016/j.cell.2008.08.021 18775299
     [Google Scholar]
  16. LocasaleJ.W. CantleyL.C. Altered metabolism in cancer.BMC Biol.2010818810.1186/1741‑7007‑8‑88 20598111
     [Google Scholar]
  17. LiuC. JinY. FanZ. The mechanism of warburg effect-induced chemoresistance in cancer.Front. Oncol.20211169802310.3389/fonc.2021.698023 34540667
     [Google Scholar]
  18. GuZ. XiaJ. XuH. FrechI. TricotG. ZhanF. NEK2 promotes aerobic glycolysis in multiple myeloma through regulating splicing of pyruvate kinase.J. Hematol. Oncol.20171011710.1186/s13045‑017‑0392‑4 28086949
     [Google Scholar]
  19. WarburgO. WindF. NegeleinE. The metabolism of tumors in the body.J. Gen. Physiol.19278651953010.1085/jgp.8.6.519 19872213
     [Google Scholar]
  20. WongN. De MeloJ. TangD. PKM2, a central point of regulation in cancer metabolism.Int. J. Cell Biol.2013201311110.1155/2013/242513 23476652
     [Google Scholar]
  21. DeBerardinisR.J. ChandelN.S. We need to talk about the Warburg effect.Nat. Metab.20202212712910.1038/s42255‑020‑0172‑2 32694689
     [Google Scholar]
  22. ZhangC. LiuN. Noncoding RNAs in the glycolysis of ovarian cancer.Front. Pharmacol.20221385548810.3389/fphar.2022.855488 35431949
     [Google Scholar]
  23. ZahraK. DeyT. Ashish; Mishra, S.P.; Pandey, U. Pyruvate kinase M2 and cancer: The role of PKM2 in promoting tumorigenesis.Front. Oncol.20201015910.3389/fonc.2020.00159 32195169
     [Google Scholar]
  24. ZhuS. GuoY. ZhangX. LiuH. YinM. ChenX. PengC. Pyruvate kinase M2 (PKM2) in cancer and cancer therapeutics.Cancer Lett.202150324024810.1016/j.canlet.2020.11.018 33246091
     [Google Scholar]
  25. DaytonT.L. GochevaV. MillerK.M. IsraelsenW.J. BhutkarA. ClishC.B. DavidsonS.M. LuengoA. BronsonR.T. JacksT. Vander HeidenM.G. Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma.Genes Dev.20163091020103310.1101/gad.278549.116 27125672
     [Google Scholar]
  26. UyedaK. Pyruvate kinase.Encyclopedia of Biological Chemistry.Elsevier201371972110.1016/B978‑0‑12‑378630‑2.00053‑0
     [Google Scholar]
  27. NoguchiT. YamadaK. InoueH. MatsudaT. TanakaT. The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters.J. Biol. Chem.198726229143661437110.1016/S0021‑9258(18)47947‑1 3654663
     [Google Scholar]
  28. IsraelsenW.J. Vander HeidenM.G. Pyruvate kinase: Function, regulation and role in cancer.Semin. Cell Dev. Biol.201543435110.1016/j.semcdb.2015.08.004 26277545
     [Google Scholar]
  29. IqbalM.A. GuptaV. GopinathP. MazurekS. BamezaiR.N.K. Pyruvate kinase M2 and cancer: An updated assessment.FEBS Lett.2014588162685269210.1016/j.febslet.2014.04.011 24747424
     [Google Scholar]
  30. MazurekS. Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells.Int. J. Biochem. Cell Biol.201143796998010.1016/j.biocel.2010.02.005 20156581
     [Google Scholar]
  31. GuptaV. BamezaiR.N.K. Human pyruvate kinase M2: A multifunctional protein.Protein Sci.201019112031204410.1002/pro.505 20857498
     [Google Scholar]
  32. SchroederP. FulzeleK. ForsythS. RibadeneiraM.D. GuichardS. WilkerE. MarshallC.G. DrakeA. FesslerR. KonstantinidisD.G. SeuK.G. KalfaT.A. Etavopivat, a pyruvate kinase activator in red blood cells, for the treatment of sickle cell disease.J. Pharmacol. Exp. Ther.2022380321021910.1124/jpet.121.000743 35031585
     [Google Scholar]
  33. ZanellaA. FermoE. BianchiP. ValentiniG. Red cell pyruvate kinase deficiency: Molecular and clinical aspects.Br. J. Haematol.20051301112510.1111/j.1365‑2141.2005.05527.x 15982340
     [Google Scholar]
  34. GraceR.F. Mark LaytonD. BarcelliniW. How we manage patients with pyruvate kinase deficiency.Br. J. Haematol.2019184572173410.1111/bjh.15758 30681718
     [Google Scholar]
  35. KoralkovaP. van SolingeW.W. van WijkR. Rare hereditary red blood cell enzymopathies associated with hemolytic anemia - pathophysiology, clinical aspects, and laboratory diagnosis.Int. J. Lab. Hematol.201436338839710.1111/ijlh.12223 24750686
     [Google Scholar]
  36. BianchiP. FermoE. GladerB. KannoH. AgarwalA. BarcelliniW. EberS. HoyerJ.D. KuterD.J. MaiaT.M. Mañu-PereiraM.M. KalfaT.A. PissardS. SegoviaJ.C. van BeersE. GallagherP.G. ReesD.C. van WijkR. Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency.Am. J. Hematol.201994114916110.1002/ajh.25325 30358897
     [Google Scholar]
  37. ImamuraK. TanakaT. Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies.J. Biochem.19727161043105110.1093/oxfordjournals.jbchem.a129852 4342282
     [Google Scholar]
  38. NetzkerR. GreinerE. EigenbrodtE. NoguchiT. TanakaT. BrandK. Cell cycle-associated expression of M2-type isozyme of pyruvate kinase in proliferating rat thymocytes.J. Biol. Chem.199226796421642410.1016/S0021‑9258(18)42712‑3 1556146
     [Google Scholar]
  39. HitosugiT. KangS. Vander HeidenM.G. ChungT.W. ElfS. LythgoeK. DongS. LonialS. WangX. ChenG.Z. XieJ. GuT.L. PolakiewiczR.D. RoeselJ.L. BoggonT.J. KhuriF.R. GillilandD.G. CantleyL.C. KaufmanJ. ChenJ. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth.Sci. Signal.2009297ra7310.1126/scisignal.2000431 19920251
     [Google Scholar]
  40. NoguchiT. InoueH. TanakaT. The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing.J. Biol. Chem.198626129138071381210.1016/S0021‑9258(18)67091‑7 3020052
     [Google Scholar]
  41. DavidC.J. ChenM. AssanahM. CanollP. ManleyJ.L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer.Nature2010463727936436810.1038/nature08697 20010808
     [Google Scholar]
  42. ChristofkH.R. Vander HeidenM.G. HarrisM.H. RamanathanA. GersztenR.E. WeiR. FlemingM.D. SchreiberS.L. CantleyL.C. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.Nature2008452718423023310.1038/nature06734 18337823
     [Google Scholar]
  43. ZhangZ. DengX. LiuY. LiuY. SunL. ChenF. PKM2, function and expression and regulation.Cell Biosci.2019915210.1186/s13578‑019‑0317‑8 31391918
     [Google Scholar]
  44. Muñoz-ColmeneroA. Fernández-SuárezA. Fatela-CantilloD. Ocaña-PérezE. Domínguez-JiménezJ.L. Díaz-IglesiasJ.M. Plasma tumor M2-Pyruvate kinase levels in different cancer types.Anticancer Res.201535742714276 26124389
     [Google Scholar]
  45. DombrauckasJ.D. SantarsieroB.D. MesecarA.D. Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis.Biochemistry200544279417942910.1021/bi0474923 15996096
     [Google Scholar]
  46. ChristofkH.R. Vander HeidenM.G. WuN. AsaraJ.M. CantleyL.C. Pyruvate kinase M2 is a phosphotyrosine-binding protein.Nature2008452718418118610.1038/nature06667 18337815
     [Google Scholar]
  47. WangC. JiangJ. JiJ. CaiQ. ChenX. YuY. ZhuZ. ZhangJ. PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer.Sci. Rep.201771288610.1038/s41598‑017‑03031‑1 28588255
     [Google Scholar]
  48. QinX. DuY. ChenX. LiW. ZhangJ. YangJ. Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown.Cell Biosci.2014412010.1186/2045‑3701‑4‑20 24735734
     [Google Scholar]
  49. XieY. YangW. TangF. ChenX. RenL. Antibacterial activities of flavonoids: Structure-activity relationship and mechanism.Curr. Med. Chem.201422113214910.2174/0929867321666140916113443 25245513
     [Google Scholar]
  50. MoulishankarA. LakshmananK. Data on molecular docking of naturally occurring flavonoids with biologically important targets.Data Brief20202910524310524310.1016/j.dib.2020.105243 32072001
     [Google Scholar]
  51. EkaluA. HabilaJ.D. Flavonoids: Isolation, characterization, and health benefits.Beni. Suef Univ. J. Basic Appl. Sci.2020914510.1186/s43088‑020‑00065‑9
     [Google Scholar]
  52. MurtiY. PathakD. PathakK. Green chemistry approaches to the synthesis of flavonoids.Curr. Org. Chem.202125172005202710.2174/1385272825666210728095624
     [Google Scholar]
  53. MurtiY. SemwalB.C. GoyalA. MishraP. Naringenin scaffold as a template for drug designing.Curr. Tradit. Med.202171284410.2174/2215083805666190617144652
     [Google Scholar]
  54. Falcone FerreyraM.L. RiusS.P. CasatiP. Flavonoids: Biosynthesis, biological functions, and biotechnological applications.Front. Plant Sci.2012322210.3389/fpls.2012.00222 23060891
     [Google Scholar]
  55. PancheA.N. DiwanA.D. ChandraS.R. Flavonoids: An overview.J. Nutr. Sci.20165e47e4710.1017/jns.2016.41 28620474
     [Google Scholar]
  56. HerrmannK. NagelC.W. Occurrence and content of hydroxycinnamic and hydroxybenzoic acid compounds in foods.Crit. Rev. Food Sci. Nutr.198928431534710.1080/10408398909527504 2690858
     [Google Scholar]
  57. BurakM. ImenY. Flavonoids and Their Antioxidant Properties.Turkiye Klin Tip Bil Derg1999
     [Google Scholar]
  58. LeeY.K. YukD.Y. LeeJ.W. LeeS.Y. HaT.Y. OhK.W. YunY.P. HongJ.T. (−)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of beta-amyloid generation and memory deficiency.Brain Res.2009125016417410.1016/j.brainres.2008.10.012 18992719
     [Google Scholar]
  59. RathodB. ChakS. PatelS. ShardA. Tumor pyruvate kinase M2 modulators: A comprehensive account of activators and inhibitors as anticancer agents.RSC Med. Chem.20211271121114110.1039/D1MD00045D 34355179
     [Google Scholar]
  60. SamecM. LiskovaA. KoklesovaL. SamuelS.M. ZhaiK. BuhrmannC. VargheseE. AbotalebM. QaradakhiT. ZulliA. KelloM. MojzisJ. ZuborP. KwonT.K. ShakibaeiM. BüsselbergD. SarriaG.R. GolubnitschajaO. KubatkaP. Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism.EPMA J.202011337739810.1007/s13167‑020‑00217‑y 32843908
     [Google Scholar]
  61. RahmanM.A. HannanM.A. DashR. RahmanM.D.H. IslamR. UddinM.J. SohagA.A.M. RahmanM.H. RhimH. Phytochemicals as a complement to cancer chemotherapy: Pharmacological modulation of the autophagy-apoptosis pathway.Front. Pharmacol.20211263962810.3389/fphar.2021.639628 34025409
     [Google Scholar]
  62. SuvarnaV. MurahariM. KhanT. ChaubeyP. SangaveP. Phytochemicals and PI3K inhibitors in cancer-An insight.Front. Pharmacol.2017891610.3389/fphar.2017.00916 29311925
     [Google Scholar]
  63. LinY. ShiR. WangX. ShenH.M. Luteolin, a flavonoid with potential for cancer prevention and therapy.Curr. Cancer Drug Targets20088763464610.2174/156800908786241050 18991571
     [Google Scholar]
  64. KelemenK. KieseckerC. ZitronE. BauerA. ScholzE. BloehsR. ThomasD. GretenJ. RemppisA. SchoelsW. KatusH.A. KarleC.A. Green tea flavonoid epigallocatechin-3-gallate (EGCG) inhibits cardiac hERG potassium channels.Biochem. Biophys. Res. Commun.2007364342943510.1016/j.bbrc.2007.10.001 17961513
     [Google Scholar]
  65. AlharbiK.S. ShaikhM.A.J. AlmalkiW.H. KazmiI. Al-AbbasiF.A. AlzareaS.I. ImamS.S. AlshehriS. GhoneimM.M. SinghS.K. ChellappanD.K. OliverB.G. DuaK. GuptaG. PI3K/Akt/mTOR pathways inhibitors with potential prospects in non-small-cell lung cancer.J. Environ. Pathol. Toxicol. Oncol.20224148510210.1615/JEnvironPatholToxicolOncol.2022042281 36374963
     [Google Scholar]
  66. SinghN.K. MujwarS. GarabaduD. In silico anti-cholinestarase activity of flavonoids: A computational approach.Asian J. Chem.201931122859286410.14233/ajchem.2019.22153
     [Google Scholar]
  67. BermanH.M. WestbrookJ. FengZ. GillilandG. BhatT.N. WeissigH. ShindyalovI.N. BourneP.E. The protein data bank.Nucleic Acids Res.200028123524210.1093/nar/28.1.235 10592235
     [Google Scholar]
  68. PettersenE.F. GoddardT.D. HuangC.C. CouchG.S. GreenblattD.M. MengE.C. FerrinT.E. UCSF Chimera?A visualization system for exploratory research and analysis.J. Comput. Chem.200425131605161210.1002/jcc.20084 15264254
     [Google Scholar]
/content/journals/lddd/10.2174/1570180820666230816090541
Loading
Flavonoids as Pyruvate Kinase M2 Inhibitor: An In silico Analysis
Letters in Drug Design & Discovery 21, 2661 (2024); https://doi.org/10.2174/1570180820666230816090541
/content/journals/lddd/10.2174/1570180820666230816090541
/content/journals/lddd/10.2174/1570180820666230816090541
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): autophagy; cancer; flavonoid; in silico; PKM2; Pyruvate kinase

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test