Fig. 1. Concept of peptide directed binding utilised in this work with in silico methods to improve the rapid and economic nature of finding new PPI modulators. Peptide 1 binds to hDM2/X, and is separated into two smaller peptides with no appreciable binding despite having two key residues each. Azide–alkyne cycloaddition (AAC) identifies small molecule fragments which restore binding affinity. The identified small molecule fragments can be combined to generate a small molecule substitute for the initial peptide.