In Silico Improvement of 3-Peptide Inhibitors of p53•hDM2 and p53•hDMX

There is great interest in molecules that inhibit the interactions between p53 and its negative regulators hDM2 and hDMX, as such molecules have validated potential against cancers that overexpress one or both of these oncoproteins.1,2 We reported that substituted 3-peptides can inhibit these interactions3,4 and, more recently, that minimally cationic 3-peptides are sufficiently cell permeable to upregulate p53-dependent genes in live cells.5,6 These observations, coupled with the established intracellular stability of -peptides7-9 and the recently reported structures of hDM210 and hDMX,11 motivated us to exploit computational methods to identify -peptides with improved potency and/or selectivity. This exercise successfully identi-fied a new 3-peptide, 53-16, that possess the desirable attributes of high affinity for hDM2 and hDMX and points to the 3,4-dichlorophenyl moiety as a novel determinant of hDMX affinity. Our computational modeling began with the application of Visual