Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies

Stapled peptides in the p53 pathway: Computer simulations reveal novel interactions of the staples with the target protein

“…While the length of the WT peptide in this study is 16 amino acids long and is three amino acids longer than in our previous study, 31 the essential characteristics that retain a stable interaction between p53 and MDM2 are the same. In WT, the backbone of peptide Glu17 interacts with the side chain of Gln72 and transiently with Lys94, while the peptide Trp23 sidechain interacts with the Leu54 back bone.…”

“…28,30,31,58 It is interesting that the poor binding peptides ST1-ST3 are characterized by poor overall helicity compared to the good binders; the best binders ST4 and ST5 are the most helical. This is in accord with the experimental observations 43 and a related simulation study of these peptides.…”

“…5J and K) and are similar to what was seen when the peptides were complexed to MDM2 and those reported earlier. 31 The major difference arises from destabilization of Leu26 which is "pushed" by the longer Met53 (this residue is Leu54 in MDM2) which leads to an attenuation in the interaction between the C-terminal region of the peptide. In the ST5-MDMX complex the staple cross links into how the positioning of the staple can be manipulated to yield to very specific and potent peptides and possibly therapeutics.…”

“…23,32 Both peptidomimetics 26,[33][34][35][36][37][38][39][40] and small molecules 25,41 have been reported to inhibit the interaction of MDM2-p53 and reactivate the transcriptional pathway; recently the mechanism underpinning the differences in the interactions of peptides and of small molecules has been described. 31,42 Clinical trials with some of these molecules are currently in progress. 32 An advantage that peptide inhibitors have over small molecules in targeting protein interaction surfaces is that they can be fine tuned for greater specificity.…”

“…24,25 and contribute the majority of the binding energy in the interaction of p53 with MDM2 and MDMX. [26][27][28][29][30][31] The reactivation of p53 regulated apoptotic pathways through the inhibition of MDM2 and MDMX has been shown to be a viable approach to suppress tumor growth in cancer cells. 23,32 Both peptidomimetics 26,[33][34][35][36][37][38][39][40] and small molecules 25,41 have been reported to inhibit the interaction of MDM2-p53 and reactivate the transcriptional pathway; recently the mechanism underpinning the differences in the interactions of peptides and of small molecules has been described.…”