QSAR: Hydropathic analysis of inhibitors of the p53-mdm2 interaction

To date, a number of p53-derived peptides have been evaluated in vitro for their ability to inhibit the carcinogenic p53-mdm2 interaction. Design of second-generation nonpeptidic compounds requires the reduction of large peptide structures down to small molecules maintaining the proper spatial arrangement of key functional groups. Molecular modeling software exists that can predict and rank intermolecular interactions from the p53-mdm2 complex crystal structure. Such analyses can yield a pharmacophore model suitable as a search query for a 3D chemical database to generate new lead compounds. As preliminary validation of this methodology, the Hydropathic INTeractions (HINT) program has been used to generate noncovalent interaction measurements between reported peptide inhibitors and mdm2. Quantitative structure-activity relationships were developed expressing peptide activity as a linear combination of hydropathic descriptors. In general, HINT measurements accurately modeled the effects of even single-atom alterations of the p53-peptide structure on activity, accounting for 70-90% of variation in experimental inhibition constants. These results surpassed those of a recently described molecular dynamics-based approach and required significantly less computation time. In conclusion, the HINT program can be integrated into the drug design cycle for next-generation p53-mdm2 complex inhibitors with confidence in its ability to simulate this noteworthy protein-protein interaction. (C) 2001 Wiley-Liss, Inc.