Molecular Modeling Approaches in the Discovery of New Drugs for Anti-Cancer Therapy: The Investigation of p53MDM2 Interaction and its Inhibition by Small Molecules (original) (raw)

Abstracl The mdm2 oncogene product, MDM2, is an ubiquitin protein ljgase that inhibits the transciptional activity of the tumor suppressor p53 and promotes its degradatiorl About 50oZ ofall human cancers present rnutations or deletions in the TP53 gene. In the remaining halfofall human neoplasias that express tbe wild-type protein, aberrations ofp53 regulators, such as MDM2, account for p53 inhibition-For this reason, designing small-molecule inhibitors oftle pS:-UDVZ protein-prctein interaction is a promising strategy for the t.eatment ofcancers retaining wild-type p53. The development ofinhibitors has been challenging. Although many small molecule MDM2 inhibito$ have shown potent vitro aitivity, only a limited number of compounds have demonstmted to possess acceptable phamacokinetiC properties for rr? ,ivo evaluation. To date, the most studied chemotypes have been c7.r-imidazolines (such as mrtlins), benzodiazepines, and spiro-oxindoles. The ci.!-imidazolines were the fint discovered potent and selective smali-molecule inhibimrs ;fthe D53-MDM2 inleraclion. and rhey continue to show therapeuric poreniial. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the ajm to better understand the behavior ofthese prcteins and to discover new small-molecule inhibitors ofthe p53-MDM2 protein-protein interaction for the treatmmt ofcancer Kenryords: p53-MDM2 interaction, molecular dynamics, based design.