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2000
Volume 32, Issue 4
  • ISSN: 0929-8665
  • E-ISSN: 1875-5305

Abstract

Purpose

This study compares the activity of BRCA-1 mimetics on WTp53 (wild-type p53 protein) and MTp53 (mutated-type p53 protein) proteins, examining the impact of TP53 mutations in breast cancer. p53 activators can be a new insight and synthesis of effective compounds for the treatment of cancer. The project contributes to the growing body of research on p53 activators and provides new insights into the design and synthesis of effective compounds for the treatment of cancer.

Methods

Molecular docking predicted binding affinity values for WTp53 and MTp53. The MM-GBSA of top compounds was run to get binding-free energies. The MD simulations were calculated, and six metal coordinates were synthesized. MTT-assays were performed with WTp53 (MCF-7) and R273H-MTp53 (MDA-MB-468) cell lines, comparing results with known p53 activator PRIMA-1 (p53-reactivation and induction of massive apoptosis-1).

Results

The p53 activators established a three-featured (2RA, 1HBA) pharmacophore. The designed compounds had better Glide gscore compared to p53 activators PRIMA-1, PRIMA-1-MET (methylated PRIMA-1), and Tamoxifen with p53 protein (WTp53, R175H and R273H MTp53). The MM-GBSA results of top compounds showed binding free energies with R175H-MTp53 (-22.24 to -75.45 kcal/mol), R273H-MTp53 (-22.8 to -36.36 kcal/mol), and WTp53 (-26.45 to -50.3 kcal/mol) compared to the p53 activator. The MD simulation of TSCO5/3KMD-MT in 100 ns indicated a stable complex when compared to TSCO5/3KMD-WT. The six metal coordinates (TSCO5-Zn, TSCO6-Zn, TSCO6-Sn, TSCO13-Zn, TSCO13-Sn, TSCO9-Sn) were synthesised. Based on results, IC for TSCO5-Zn (WTp53: 0.089 μM, MTp53: 0.074 μM) and TSCO5-Sn (WTp53: 0.092 μM, MTp53: 0.073 μM) have shown significant cytotoxicity.

Conclusion

As compared to PRIMA-1, the designed compound TSCO5 metal coordinates have shown good and activity on mutated p53 cell lines and are more potent than the p53 activator PRIMA-1.

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References

  1. NegiP. ChekeR.S. PatilV.M. Recent advances in pharmacological diversification of Src family kinase inhibitors.Egypt. J. Med. Hum. Genet.20212215210.1186/s43042‑021‑00172‑x
     [Google Scholar]
  2. 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]
  3. WeinbergR.A. The Biology of Cancer.Bioscience.2nd Ed.New YorkW.W. Norton & Company201396010.1201/9780429258794
     [Google Scholar]
  4. SoussiT. WimanK.G. TP53: An oncogene in disguise.Cell Death Differ.20152281239124910.1038/cdd.2015.53 26024390
     [Google Scholar]
  5. KontomanolisN.E. KoutrasA. SyllaiosA. SchizasD. KalagasidouS. PagkalosA. AlatzidouD. KantariP. NtounisT. FasoulakisZ. Basic principles of molecular biology of cancer cell-Molecular cancer indicators.JBUON202126517231734 34761575
     [Google Scholar]
  6. KaleJ. OsterlundE.J. AndrewsD.W. BCL-2 family proteins: Changing partners in the dance towards death.Cell Death Differ.2018251658010.1038/cdd.2017.186 29149100
     [Google Scholar]
  7. KumarV. AbbasA.K. AsterJ.C. Robbins & Cotran Pathologic Basis of Disease.9th EditionPhiladelphia, PAElsevier2015
     [Google Scholar]
  8. ChiangY.T. ChienY.C. LinY.H. WuH.H. LeeD.F. YuY.L. The function of the mutant p53-R175H in cancer.Cancers20211316408810.3390/cancers13164088 34439241
     [Google Scholar]
  9. P, S.S.; Naresh, P.; A, J.; Wadhwani, A.; M, S.K.; Jubie, S. Dual modulators of p53 and cyclin D in ER alpha signaling by albumin nanovectors bearing zinc chaperones for er-positive breast cancer therapy.Mini Rev. Med. Chem.202121779280210.2174/1389557520999201124212347 33238842
     [Google Scholar]
  10. RivlinN. BroshR. OrenM. RotterV. Mutations in the p53 tumor suppressor gene: Important milestones at the various steps of tumorigenesis.Genes Cancer20112446647410.1177/1947601911408889 21779514
     [Google Scholar]
  11. BerksonR.G. HollickJ.J. WestwoodN.J. WoodsJ.A. LaneD.P. LainS. Pilot screening programme for small molecule activators of p53.Int. J. Cancer2005115570171010.1002/ijc.20968 15729694
     [Google Scholar]
  12. KlimovichB. MeyerL. MerleN. NeumannM. KönigA.M. AnanikidisN. KeberC.U. ElmshäuserS. TimofeevO. StieweT. Partial p53 reactivation is sufficient to induce cancer regression.J. Exp. Clin. Cancer Res.20224118010.1186/s13046‑022‑02269‑6 35232479
     [Google Scholar]
  13. EsmailS.A.A. ShamsiM. ChenT. asbahy, A.W.M. Design, synthesis and characterization of tin‐based cancer chemotherapy drug entity: In vitro DNA binding, cleavage, induction of cancer cell apoptosis by triggering DNA damage‐mediated p53 phosphorylation and molecular docking.Appl. Organomet. Chem.2019331e465110.1002/aoc.4651
     [Google Scholar]
  14. BlandenA.R. YuX. BlayneyA.J. DemasC. HaJ.H. LiuY. WithersT. CarpizoD.R. LohS.N. Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants.eLife20209e6148710.7554/eLife.61487 33263541
     [Google Scholar]
  15. DuffyM.J. SynnottN.C. O’GradyS. CrownJ. Targeting p53 for the treatment of cancer.Semin. Cancer Biol.202279586710.1016/j.semcancer.2020.07.005 32741700
     [Google Scholar]
  16. LiX.L. ZhouJ. ChanZ.L. ChooiJ.Y. ChenZ.R. ChngW.J. PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms.Oncotarget2015634366893669910.18632/oncotarget.5385 26452133
     [Google Scholar]
  17. MenichiniP. MontiP. SpecialeA. CutronaG. MatisS. FaisF. TaianaE. NeriA. BombenR. GentileM. GatteiV. FerrariniM. MorabitoF. FronzaG. Antitumor effects of PRIMA-1 and PRIMA-1Met (APR246) in hematological malignancies: Still a mutant p53-dependent affair?Cells20211019810.3390/cells10010098 33430525
     [Google Scholar]
  18. LozanoG. Restoring p53 in cancer: The promises and the challenges.J. Mol. Cell Biol.201911761561910.1093/jmcb/mjz063 31283825
     [Google Scholar]
  19. LambertJ.M.R. GorzovP. VeprintsevD.B. SöderqvistM. SegerbäckD. BergmanJ. FershtA.R. HainautP. WimanK.G. BykovV.J.N. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain.Cancer Cell200915537638810.1016/j.ccr.2009.03.003 19411067
     [Google Scholar]
  20. HaJ.H. PrelaO. CarpizoD.R. LohS.N. p53 and Zinc: A malleable relationship.Front. Mol. Biosci.2022989588710.3389/fmolb.2022.895887 35495631
     [Google Scholar]
  21. YuX. BlandenA. TsangA.T. ZamanS. LiuY. GilleranJ. BencivengaA.F. KimballS.D. LohS.N. CarpizoD.R. Thiosemicarbazones functioning as zinc metallochaperones to reactivate mutant p53.Mol. Pharmacol.201791656757510.1124/mol.116.107409 28320780
     [Google Scholar]
  22. BaiX.G. ZhengY. QiJ. Advances in thiosemicarbazone metal complexes as anti-lung cancer agents.Front. Pharmacol.202213101895110.3389/fphar.2022.1018951 36238553
     [Google Scholar]
  23. KastenhuberE.R. LoweS.W. Putting p53 in context.Cell201717061062107810.1016/j.cell.2017.08.028 28886379
     [Google Scholar]
  24. ChenY. DeyR. ChenL. Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer.Structure201018224625610.1016/j.str.2009.11.011 20159469
     [Google Scholar]
  25. Schrödinger (2022)Schrödinger Suite 2022-1 version 5.7. Release 2022-1.New York, USASchrödinger LLC2022
     [Google Scholar]
  26. ACD/Labs2021.2.1, Advanced Chemistry Development; Inc.Toronto, ON, CanadaACD/Labs2021
     [Google Scholar]
  27. Schneidman-DuhovnyD. InbarY. NussinovR. WolfsonH.J. PatchDock and SymmDock: servers for rigid and symmetric docking.Nucl. Acids Res.200233W636-367
     [Google Scholar]
  28. DuhovnyS.D. DrorO. InbarY. NussinovR. WolfsonH.J. Deterministic pharmacophore detection via multiple flexible alignment of drug-like molecules.J. Comput. Biol.200815773775410.1089/cmb.2007.0130 18662104
     [Google Scholar]
  29. DuhovnyS.D. DrorO. InbarY. NussinovR. WolfsonH.J. PharmaGist: A webserver for ligand-based pharmacophore detection.Nucleic. Acids. Res.200836Web Server issueW223W22810.1093/nar/gkn187
     [Google Scholar]
  30. ME. SwaroopA.K. PatnaikS.K. KumarR.R. KT.P. NaikM.R. JubieS. A novel family of small molecule HIF-1 alpha stabilizers for the treatment of diabetic wounds; an integrated in silico, in vitro, and in vivo strategy.RSC Advances20221248312933130210.1039/D2RA05364K 36349012
     [Google Scholar]
  31. ShyamS.P. NareshP. NatarajanJ. WadhwaniA. JubieS. Potential coumarin thiosemicarbazone hybrids as BRCA-1 mimetics for ER positive breast cancer therapy: An in silico approach.J. Medi. Pharm. Alli. Sci.2021104138310.22270/jmpas.V10I4.1383
     [Google Scholar]
  32. JubieS. PottabathulaS.S. SwaroopA.K. DhanabalP. (2-((E)-7-hydroxy-4-methyl-2H-chromen-2-ylidene)-N-((E)-2-nitrobenzylidene) hydra-zine-1-carbothioamide), BRCA-1 mimetic useful for breast cancer treatment.PCT202241013361 A2022
  33. FuX. TanW. SongQ. PeiH. LiJ. BRCA1 and breast cancer: molecular mechanisms and therapeutic strategies.Front. Cell Dev. Biol.20221081345710.3389/fcell.2022.813457 35300412
     [Google Scholar]
  34. PengL. XuT. LongT. ZuoH. Association between BRCA status and p53 status in breast cancer: A meta-analysis.Med. Sci. Monit.2016221939194510.12659/MSM.896260 27272763
     [Google Scholar]
  35. ReleaseS. 2022-1: LigPrep.New York, NYSchrödinger, LLC2022
     [Google Scholar]
  36. SastryM.G. AdzhigireyM. DayT. AnnabhimojuR. ShermanW. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments.J. Comput. Aided Mol. Des.201327322123410.1007/s10822‑013‑9644‑8 23579614
     [Google Scholar]
  37. ReleaseS. 2022-1: Protein Preparation Wizard.New York, NYPrime, Schrödinger, LLC2022
     [Google Scholar]
  38. ReleaseS. 2022-1: SiteMap.New York, NYSchrödinger, LLC2022
     [Google Scholar]
  39. HalgrenT.A. Identifying and characterizing binding sites and assessing druggability.J. Chem. Inf. Model.200949237738910.1021/ci800324m 19434839
     [Google Scholar]
  40. HalgrenT. New method for fast and accurate binding-site identification and analysis.Chem. Biol. Drug Des.200769214614810.1111/j.1747‑0285.2007.00483.x 17381729
     [Google Scholar]
  41. YangY. YaoK. RepaskyM.P. LeswingK. AbelR. ShoichetB.K. JeromeS.V. Efficient exploration of chemical space with docking and deep learning.J. Chem. Theory Comput.202117117106711910.1021/acs.jctc.1c00810 34592101
     [Google Scholar]
  42. FriesnerR.A. MurphyR.B. RepaskyM.P. FryeL.L. GreenwoodJ.R. HalgrenT.A. SanschagrinP.C. MainzD.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.J. Med. Chem.200649216177619610.1021/jm051256o 17034125
     [Google Scholar]
  43. HalgrenT.A. MurphyR.B. FriesnerR.A. BeardH.S. FryeL.L. PollardW.T. BanksJ.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.J. Med. Chem.20044771750175910.1021/jm030644s 15027866
     [Google Scholar]
  44. FriesnerR.A. BanksJ.L. MurphyR.B. HalgrenT.A. KlicicJ.J. MainzD.T. RepaskyM.P. KnollE.H. ShelleyM. PerryJ.K. ShawD.E. FrancisP. ShenkinP.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.J. Med. Chem.20044771739174910.1021/jm0306430 15027865
     [Google Scholar]
  45. ReleaseS. 2022-1: Glide.New York, NYSchrödinger, LLC2022
     [Google Scholar]
  46. McConkeyB.J. SobolevV. EdelmanM. The performance of current methods in ligand–protein docking.Curr. Sci.2002837845856
     [Google Scholar]
  47. ReleaseS. 2022-1: QikProp.New York, NYSchrödinger, LLC2021
     [Google Scholar]
  48. IoakimidisL. ThoukydidisL. MirzaA. NaeemS. ReynissonJ. Benchmarking the reliability of qikprop. correlation between experimental and predicted values.QSAR Comb. Sci.200827444545610.1002/qsar.200730051
     [Google Scholar]
  49. RomanD.L. RomanM. SomC. SchmutzM. HernandezE. WickP. CasaliniT. PeraleG. OstafeV. IsvoranA. Computational assessment of the pharmacological profiles of degradation products of chitosan.Front. Bioeng. Biotechnol.2019721410.3389/fbioe.2019.00214 31552240
     [Google Scholar]
  50. WangE. SunH. WangJ. WangZ. LiuH. ZhangJ.Z.H. HouT. End point binding free energy calculation with MM/PBSA and MM/GBSA: Strategies and applications in drug design.Chem. Rev.2019119169478950810.1021/acs.chemrev.9b00055 31244000
     [Google Scholar]
  51. JacobsonM.P. PincusD.L. RappC.S. DayT.J.F. HonigB. ShawD.E. FriesnerR.A. A hierarchical approach to all‐atom protein loop prediction.Proteins200455235136710.1002/prot.10613 15048827
     [Google Scholar]
  52. JacobsonM.P. FriesnerR.A. XiangZ. HonigB. On the role of the crystal environment in determining protein side-chain conformations.J. Mol. Biol.2002320359760810.1016/S0022‑2836(02)00470‑9 12096912
     [Google Scholar]
  53. ReleaseS. 2022-1: Prime.New York, NYSchrödinger, LLC2022
     [Google Scholar]
  54. HarderE. DammW. MapleJ. WuC. ReboulM. XiangJ.Y. WangL. LupyanD. DahlgrenM.K. KnightJ.L. KausJ.W. CeruttiD.S. KrilovG. JorgensenW.L. AbelR. FriesnerR.A. OPLS3: A force field providing broad coverage of drug-like small molecules and proteins.J. Chem. Theory Comput.201612128129610.1021/acs.jctc.5b00864 26584231
     [Google Scholar]
  55. BowersK. ChowE. XuH. DrorR. EastwoodM. GregersenB. Scalable algorithms for molecular dynamics simulations on commodity clusters.ACM/IEEE SC 2006 Conference (SC'06)2006435410.1109/SC.2006.54
     [Google Scholar]
  56. ReleaseS. Desmond Molecular Dynamics System; Maestro-Desmond Interoperability Tools.New York, NYSchrödinger2019
     [Google Scholar]
  57. JubieS. SundarS. YadavN. NareshP. WadhwaniA. NatarajanJ. A new class of coumate benzimidazole hybrids as brca 1 mimetics through unconventional binding mode; synthesis and preliminary cytotoxicity screening.Curr. Computeraided Drug Des.202116678680110.2174/1573409916666191231102046 31889499
     [Google Scholar]
  58. AkeyS.K. PatnaikS.K. VasanthP. KumarP. JowaharN. SelvarajJ. Synthesis and evaluation of novel flavonoid metal complexes as immune boosters for dual modulation of IL-6 pathway in SARS-CoV-2 therapy: A combined in silico and in vitro approaches. Res.Squar2022Available from: https://europepmc.org/article/ppr/ppr487653 (Accessed on: 10 May 2023).
     [Google Scholar]
  59. GerlierD. ThomassetN. Use of MTT colorimetric assay to measure cell activation.J. Immunol. Methods1986941-2576310.1016/0022‑1759(86)90215‑2 3782817
     [Google Scholar]
  60. ZhangS. CarlsenL. BorreroH.L. SeyhanA.A. TianX. DeiryE.W.S. Advanced strategies for therapeutic targeting of wild-type and mutant p53 in cancer.Biomolecules202212454810.3390/biom12040548 35454137
     [Google Scholar]
  61. ZhouY. WangK. ZhouN. HuangT. ZhuJ. LiJ.C. Butein activates p53 in hepatocellular carcinoma cells via blocking MDM2-mediated ubiquitination.OncoTargets Ther.2018112007201510.2147/OTT.S160119 29670376
     [Google Scholar]
  62. PatrícioR.P.S. VideiraP.A. PereiraF. A computer-aided drug design approach to discover tumour suppressor p53 protein activators for colorectal cancer therapy.Bioorg. Med. Chem.20225311653010.1016/j.bmc.2021.116530 34861473
     [Google Scholar]
  63. LiuB. ZhangM. LiuS. YingJ. ZhangJ. KuriharaH. ZhengW. HeR.R. ZhuR. Diosmetin, a potential p53 activator, performs anticancer effect by regulating cell cycling and cell proliferation in hepg2 cells.Protein Pept. Lett.201724541341810.2174/0929866524666170223094634 28240165
     [Google Scholar]
  64. ZhouX. ZouL. ChenW. YangT. LuoJ. WuK. ShuF. TanX. YangY. CenS. LiC. MaoX. Flubendazole, FDA-approved anthelmintic, elicits valid antitumor effects by targeting p53 and promoting ferroptosis in castration-resistant prostate cancer.Pharmacol. Res.202116410530510.1016/j.phrs.2020.105305 33197601
     [Google Scholar]
  65. ZhangQ. ZengS.X. ZhangY. ZhangY. DingD. YeQ. MerouehS.O. LuH. A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.EMBO Mol. Med.20124429831210.1002/emmm.201100211 22331558
     [Google Scholar]
  66. RamosH. SoaresM.I.L. SilvaJ. RaimundoL. CalheirosJ. GomesC. ReisF. MonteiroF.A. NunesC. ReisS. BoscoB. PiazzaS. DominguesL. ChlapekP. VlcekP. FabianP. RajadoA.T. CarvalhoA.T.P. VeselskaR. IngaA. Pinho e MeloT.M.V.D. SaraivaL. A selective p53 activator and anticancer agent to improve colorectal cancer therapy.Cell Rep.202135210898210.1016/j.celrep.2021.108982 33852837
     [Google Scholar]
  67. SahaM.N. ChenY. ChenM-H. ChenG. ChangH. Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents.Br. J. Cancer201411092224223110.1038/bjc.2014.164 24691427
     [Google Scholar]
  68. SynnottN.C. BauerM.R. MaddenS. MurrayA. KlingerR. O’DonovanN. O’ConnorD. GallagherW.M. CrownJ. FershtA.R. DuffyM.J. Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Preclinical investigation with the anti-p53 drug, PK11007.Cancer Lett.20184149910610.1016/j.canlet.2017.09.053 29069577
     [Google Scholar]
  69. AbbasiM. AliabadiS.H. HassanzadehF. AmanlouM. Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening.J. Mol. Graph. Model.20156118619510.1016/j.jmgm.2015.08.001 26277488
     [Google Scholar]
  70. LaddsM.J.G.W. LaínS. Small molecule activators of the p53 response.J. Mol. Cell Biol.201911324525410.1093/jmcb/mjz006 30689917
     [Google Scholar]
  71. ZacheN. LambertJ.M.R. RökaeusN. ShenJ. HainautP. BergmanJ. WimanK.G. BykovV.J.N. Mutant p53 targeting by the low molecular weight compound STIMA‐1.Mol. Oncol.200821708010.1016/j.molonc.2008.02.004 19383329
     [Google Scholar]
  72. LainS. HollickJ.J. CampbellJ. StaplesO.D. HigginsM. McCarthyA. AppleyardV. MurrayK.E. BakerL. ThompsonA. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator.Can. Cell2008135-245446310.1016/j.ccr.2008.03.004
     [Google Scholar]
  73. DrorO. DuhovnyS.D. InbarY. NussinovR. WolfsonH.J. Novel approach for efficient pharmacophore-based virtual screening: Method and applications.J. Chem. Inf. Model.200949102333234310.1021/ci900263d 19803502
     [Google Scholar]
  74. The PyMOL Molecular Graphics System2023Available from: https://pymol.org/support.html (Accessed 6 Mar 2023).
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Comparative In silico and In vitro Studies of Novel Zinc/Tin Metal Coordinates Bearing BRCA-1 Mimetics on WTp53 and MTp53 Proteins
PPL 32, 253 (2025); https://doi.org/10.2174/0109298665361116250121103146
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  • Article Type:     Research Article
Keyword(s): Breast cancer; MCF-7; MDA-MB-468; molecular dynamics; p53 protein; pharmacophore; PRIMA-1

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