Molecular Modeling Approaches in the Discovery of New Drugs for Anti-Cancer Therapy: The Investigation of p53-MDM2 Interaction and its Inhibition by Small Molecules

Author(s): A. Lauria, M. Tutone, M. Ippolito, L. Pantano, A. M. Almerico.

Journal Name: Current Medicinal Chemistry

Volume 17 , Issue 28 , 2010

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Abstract:

The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regulators, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53- MDM2 interaction, and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.

Keywords: p53-MDM2 interaction, molecular dynamics, pharmacophore-based approaches, molecular docking, structurebased design

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Article Details

VOLUME: 17
ISSUE: 28
Year: 2010
Page: [3142 - 3154]
Pages: 13
DOI: 10.2174/092986710792232021
Price: $58

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