Identification of selective protein–protein interaction inhibitors using efficient in silico peptide-directed ligand design

Abstract

Development of selective hDM2/X p53 inhibitors is key to further develop this anticancer target. This method displayed a 50% success rate and identified hDMX selective compounds.

Proteomimetic surface fragments distinguish targets by function

“…32 Recent theoretical and experimental results strongly support that fragment-centric design built on recognition elements of reduced structural complexity is highly promising for the construction of surface mimetic ligands. [33][34][35] It is also in accord with the fragment-centric approach that protein interfaces are highly degenerate and strongly interconnected, and interface geometries are not dominated locally by specic secondary structure types. 36,37 To develop the fragment-centric concept further, the present study aimed to nd minimal motifs that can serve as local surface mimetics (LSM) with sufficient affinity to probe otherwise undruggable protein surfaces.…”

In Silico Peptide-Directed Ligand Design Complements Experimental Peptide-Directed Binding for Protein-Protein Interaction Modulator Discovery

“…This library was redocked to the protein target and the top 10 results were chosen for synthesis. Our report of in silico peptide-directed ligand design 28 demonstrated a higher efficiency at discovering small molecule inhibitors of PPIs when compared to the analogous experimental peptide-directed binding. 24 The in silico method required the preparation of only 20 compounds to obtain a 50% hit rate of compounds which demonstrated an IC50 < 100 μM in in vitro protein fluorescence anisotropy assays.…”

In silico peptide-directed ligand design complements experimental peptide-directed binding for protein–protein interaction modulator discovery

“…To further improve the efficiency of this method we applied a fully computational peptide-directed ligand design to the PPIs of hDM2/hDMX and p53. 28 This process mirrored that of peptide-directed binding, but performed steps 1–3 ( Fig. 1 ) computationally, identifying a number of small molecules triazoles for synthesis.…”