How Nutlin-3 disrupts the MDM2-p53 interaction: A theoretical investigation

Shah Md, Abdur Rauf, Hiromitsu Takaba, Carlos A. Del Carpio, Akira Miyamoto

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The tumor suppressor protein p53 is inhibited while mouse double minute 2 (MDM2) protein binds on its transactivation domain. Overexpression of MDM2 impairs p53 function and are observed in many human tumors. Disruption of MDM2-p53 interaction leads to increased p53 level and restores p53 transcriptional activity. Restoration of p53 activity through inhibiting the interaction between p53 and MDM2 represents a promising approach for cancer therapy. A number of small-molecule p53-MDM2 binding inhibitors have been developed during the past several years. Nutlin-3 has shown a potent and selective small-molecule MDM2 antagonist which has a considerable promise in pre-clinical studies. In this study we investigated theoretically the interaction of Nutlin-3 with MDM2 at atomistic level, and compared to the interaction of p53 with MDM2 to explore the molecular basis of inhibition. In MDM2-p53 model, there are three hydrogen bonding interactions between MDM2 and p53. The lengths of the hydrogen bonds are found to be 2.45, 2.46, and 1.89 Å whereas interaction energies are -3.82, -3.76, and -5.32 kcal/mol, respectively. The sum of three hydrogen bonding energy is -12.90 kcal/mol. On the other hand, in MDM2-Nutlin-3 model there are four hydrogen bond interactions between MDM2 and Nutlin-3. The bond lengths are found to be 2.29, 1.77, 2.48, and 2.39 Å whereas interaction energies are -4.21, -6.63, -3.65, and -3.63 kcal/mol, respectively. The sum of three hydrogen bonding energy is -18.12 kcal/mol. From the comparison between two models, it is revealed that MDM2-Nutlin3 model has four hydrogen bonds whereas MDM2-p53 model has three hydrogen bonds. The interaction energy in MDM2-Nutlin-3 is relatively more stable than MDM2-p53 interaction. Due to stronger hydrogen bond interaction with higher interaction energy, Nutlin-3 blocks the p53-binding pocket of MDM2 and thus disrupts the MDM2-p53 interaction and helps to activate p53 pathway of apoptosis.

Original languageEnglish
Pages (from-to)1998-2006
Number of pages9
JournalMedicinal Chemistry Research
Volume23
Issue number4
DOIs
Publication statusPublished - 2014 Jan 1

Keywords

  • Hydrogen bonds
  • MDM2-Nutlin3 interaction
  • MIAX
  • UA-QCMD
  • p53

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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