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.

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The emergence of drug-resistant mutants of HIV-1 is a tragic effect associated with conventional long-treatment therapies against acquired immunodeficiency syndrome. These mutations frequently involve the aspartic protease encoded by the virus; knowledge of the molecular mechanisms underlying the conformational changes of HIV-1 protease mutants may be useful in developing more effective and longer lasting treatment regimes. The flap regions of the protease are the target of a particular type of mutations occurring far from the active site. These mutations modify the affinity for both substrate and ligands, thus conferring resistance. In this work, molecular dynamics simulations were performed on a native wild type HIV-1 protease and on the drug-resistant M46I/G51D double mutant. The simulation was carried out for a time of 3.5 ns using the GROMOS96 force field, with implementation of the SPC216 explicit solvation model. The results show that the flaps may exist in an ensemble of conformations between a "closed" and an "open" conformation. The behaviour of the flap tips during simulations is different between the native enzyme and the mutant. The mutation pattern leads to stabilization of the flaps in a semi-open configuration.

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