Effect of Nutlin-3a on stability of p53-MDM2 complex

<sec>P53 is well recognized to be a tumor suppressor protein. In response the external stress or environmental perturbation, p53 can promote transcription of various target genes downstream, thus regulating cell cycle, apoptosis, DNA repair, and angiogenesis. However, activation further activated by another protein, MDM2, which negatively regulates level inverse reduces p53. This phenomenon novel potential promising strategy for cancer therapy, i.e. restoring activity pathway through competitive inhibitors that occupy p53-binding site MDM2 inhibit interaction between MDM2.</sec><sec>Recently, kinds have been designed this purpose. The Nutlin family group investigated inhibitors, shows high efficiency suppression. Nutlin-3a mimics MDM2-binding essentially, blocks binding Once getting free from rapidly accumulates in nuclei cells, are activated, thereby resulting cell-cycle arrest apoptosis. our previous papers, we competition mechanism Nutlin3 <i>in vitro</i> using molecular dynamics simulations. We found bind faster than prevent when equal distance MDM2. also p53-MDM2 complex disturb weaken interactions underlying mechanisms instability vivo</i> still unclear. And these variety specificities biological toxicities environment.</sec><sec>In study, go step investigate effect on stability physiological environment with aid mechanics/generalized borne surface area (MM/GBSA) method. simulations, molecules randomly put around pocket initial stages examine among p53, analyze MDM2.</sec><sec>We find induce centroid increase. Importantly, show weakens affinity complex. Consistently, breaks hydrogen bond Phe19-Gln72 salt bridge Glu17-Lys94, From systematic biology point view, regulation extremely sensitive strength interaction. avianization restore its suppression functions development.</sec><sec>This study may helpful understanding mediated searching effective interaction.</sec>