Abstract
Inhibition of the MDM2–p53 interaction has been becomes a new therapeutic strategy to activate wild-type p53 in tumors. Molecular dynamics (MD) simulations were used to study the effects of quercetin and taxifolin on MDM2–p53 complex. We found that binding of ligands (quercetin and taxifolin) led to the dissociation of MDM2–p53 complex. Analyses of the hydrophobic contacts between the inhibitors and MDM2–p53 were performed, and the results suggested that these ligands form stable hydrophobic interactions with MDM2 which led to complete disruption of MDM2–p53 hydrophobic interactions and dissociation of p53 from the complex. Our study suggests that the pi–pi stacking between Tyr 51 of MDM2 and aromatic rings of ligands is the critical event in MDM2–p53 dissociation.
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References
Accelrys Software Inc (2011) Discovery studio modeling environment, release 3.1, San Diego
Allen JG, Bourbeau MP, Wohlhieter GE (2009) Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein–protein interaction. J Med Chem 52:7044–7053
Bautista AD, Appelbaum JS, Craig CJ et al (2010) Bridged α3- peptide Inhibitors of p53–hDM2 complexation: correlation between affinity and cell permeability. J Am Chem Soc 132:2904–2906
Berendsen HJC, Van der Spoel D, Van Drunen R (1995) GROMACS—A Message-passing parallel molecular dynamics implementation. Phys Commun 91:43–56
Bharatham N, Chi S, Yoon HS (2011) Molecular basis of Bcl-XL-p53 interaction: insights from molecular dynamics simulations. 6:e26014
Chen J, Wang J, Xu B et al (2011) Insight into mechanism of small molecule inhibitors of the MDM2–p53 interaction: molecular dynamics simulation and free energy analysis. J Mol Graph Model 30:46–53
Chene P (2003) Inhibiting the p53–MDM2 interaction: an important target for cancer. Clin Cancer Res 14:5318–5324
Dastidar SG, Lane DP, Verma CS (2009) Modulation of p53 binding to MDM2: computational studies reveal important role of Tyr 100, BMC bioinformatics Proceedings
Espinoza-FonsecaJose LM, García-Machorro J (2008) Aromatic–aromatic interactions in the formation of the MDM2–p53 complex. Biochem Biophys Res Comm 370:547–551
Espinoza-FonsecaJose LM, Trujillo-Ferrara G (2006) Conformational changes of the p53-binding cleft of MDM2 revealed by molecular dynamics simulations. Biopolymers 83:365–373
Fasan R, Dias RLA, Moehle K et al (2004) Using a ß-hairpin to mimic alpha-helix-novel cyclic peptidomimetic inhibitors of the p53–HDM2 protein–protein interaction. Angew Chem Int Ed 43:2109–2112
Koblish HK, Zhao S, Franks CF et al (2006) Benzodiazepinedione inhibitors of the Hdm2: p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 5:160–169
Kritzer JA, Lear JD, Hodsdon ME, Schepartz A (2004) Helical α-peptide inhibitors of the p53–hDM2 interaction. J Am Chem Soc 126:9468–9469
Lee SB, Cha KH, Selenge D et al (2007) The Chemopreventive Effect of Taxifolin Is Exerted through ARE-Dependent Gene Regulation. Biol Pharm Bull 30:1074–1079
Levine AJ (1997) P53, the cellular gatekeeper for growth and division. Cell 88:323–331
Lindah E, Hess B, Van der Spoel D (2001) Gromacs 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7:306–317
Moll UM, Petrenko O (2003) The MDM2-p53 Interaction. Mol Cancer Res 1:1001–1008
Morris GM, Goodsell DS, Halliday RS (1998) Automated Docking Using a Lamarckian Genetic Algorithm and Empirical Binding Free Energy Function. J Comp Chem 19:1639–1662
Morris GM, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791
Popowicz GM, Czarna A, Wolf S et al (2010) Structure of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53–MDMX/MDM2 antagonist drug discovery. Cell Cycle 9:1104–1111
Schuttelkopf AW, van Aalten (2004) DMF PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr 60:1355–1363
Seufi AM, Ibrahim SS, Elmaghraby TK et al (2009) Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. J Exp Clin Cancer Res 28:80. doi:10.1186/1756-9966-28-80
Shangary S, Wang SM (2008) Targeting the MDM2–p53 interaction for cancer therapy. Clin Cancer Res 14(17):5318–5324
Shangary S, Wang SM (2009) Small-molecule inhibitors of the MDM2–p53 protein–protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 49:223–241
Stoll R, Renner C, Hansen S et al (2001) Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53. Biochem 40:336–344
Van Gunsteren WF, Billeter SR, Eising AA et al (1996) Biomolecular simulation: the GROMOS96 manual and user guide. Vdf Hochschulverlag AG, Zurich
Van Gunsteren WF, Daura X, Mark AE (1998) The GROMOS force field. In: Von Rague Schleyer P (ed) Encyclopedia of computational chemistry, vol 2. Wiley and Sons, Chichester, pp 1211–1216
Vassilev LT, Vu BT, Graves B et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848
Vogelstein B, Lane D, Levine AJ (2000) The p53 tumour-suppressor gene integrates numerous signals that control cell life and death, as when a highly connected node in the Internet breaks down, the disruption of p53 has severe consequences. Nature 408:307–310
Zhao J, Wang M, Chen J et al (2002) The initial evaluation of non-peptidic small-molecule HDM2 inhibitors based on p53–HDM2 complex structure. Cancer Lett 183:69–77
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One of the authors (Sharad Verma) is thankful to the Council of Scientific and Industrial Research (CSIR), India for providing Senior Research Fellowship.
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Verma, S., Singh, A. & Mishra, A. Quercetin and taxifolin completely break MDM2–p53 association: molecular dynamics simulation study. Med Chem Res 22, 2778–2787 (2013). https://doi.org/10.1007/s00044-012-0274-9
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DOI: https://doi.org/10.1007/s00044-012-0274-9