In Silico Improvement of β³-Peptide Inhibitors of p53•hDM2 and p53•hDMX

There is great interest in molecules capable of inhibiting the interactions between p53 and its negative regulators hDM2 and hDMX, as these molecules have validated potential against cancers in which one or both oncoproteins are overexpressed. We reported previously that appropriately substituted β3-peptides inhibit these interactions and, more recently, that minimally cationic β3-peptides are sufficiently cell permeable to upregulate p53-dependent genes in live cells. These observations, coupled with the known stability of β-peptides in a cellular environment, and the recently reported structures of hDM2 and hDMX, motivated us to exploit computational modeling to identify β-peptides with improved potency and/or selectivity. This exercise successfully identified a new β3-peptide, β53-16, that possesses the highly desirable attribute of high affinity for both hDM2 and hDMX and identifies the 3,4-dichlorophenyl moiety as a novel determinant of hDMX affinity.