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
- Autori: Lauria, A; Tutone, M; Ippolito, M; Pantano, L; Almerico, AM
- Anno di pubblicazione: 2010
- Tipologia: Articolo in rivista (Articolo in rivista)
- Parole Chiave: Molecular Modeling, New Drugs for Anti-Cancer Therapy, p53-MDM2 Interaction
- OA Link: http://hdl.handle.net/10447/51317
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 regula- tors, 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.