title: 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.
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.
authors.affiliation: Dipartimento Farmacochimico, Tossicologico e Biologico, Università di Palermo, Palermo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lauria
authors.forename: M
authors.initials: M
authors.lastname: Tutone
authors.forename: M
authors.initials: M
authors.lastname: Ippolito
authors.forename: L
authors.initials: L
authors.lastname: Pantano
authors.forename: A M
authors.initials: AM
authors.lastname: Almerico
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D001570:Benzodiazepinones / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D048288:Imidazolines / Q000737:chemistry / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy; D000078183:Oxindoles; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D048288:Imidazolines; D007211:Indoles; D000078183:Oxindoles; D016159:Tumor Suppressor Protein p53; C022960:2-oxindole; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2