Restoration of p53-DNA interaction loss upon R273H mutation by CP-31398: An ultra accelerated quantum chemical molecular dynamics approach

Shah Md Abdur Rauf, Kamlesh Kumar Sahu, Hideyuki Tsuboi, Nozomu Hatakeyama, Akira Endou, Hiromitsu Takaba, Carlos A. Del Carpio, Akira Miyamoto

Research output: Contribution to journalArticle

Abstract

The mutation of Arginine273 to Histidine in the DNA binding domain of p53 is one of the most common mutations found in human cancer. Though R273H mutation retains wild-type conformation, the sequence-specific DNA binding is impaired and subsequently lack of transactivation function and the ability to suppress cell growth. CP-31398 can restore DNA binding activity to mutant p53 has shown by a chromatin immunoprecipitation assay but the underlying mechanism at atomistic level is not well understood. Our aim is to investigate theoretically the effect of R273H mutation on DNA binding and the mechanism of restoration of DNA binding by CP-31398, using docking and newly developed ultra accelerated quantum chemical molecular dynamics. Our results show that due to R273H mutation, p53 lost two hydrogen bonds with DNA at the binding site during interaction. CP-31398 helps to reestablish the lost hydrogen bond interactions at p53-DNA binding site, thus restore DNA binding activity and transcriptional activity. This will provide a deeper insight to structure-based drug designing.

Original languageEnglish
Pages (from-to)239-244
Number of pages6
JournalMedicinal Chemistry Research
Volume21
Issue number2
DOIs
Publication statusPublished - 2012 Feb 1

Keywords

  • Docking
  • Mutation
  • P53-DNA interaction
  • Quantum chemical molecular dynamics

ASJC Scopus subject areas

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

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