β‐Strand Mimicry: Exploring Oligothienylpyridine Foldamers

Protein–protein interactions (PPIs) are involved in many cellular processes; consequently, the discovery of small molecules as modulators of PPIs has become an important challenge in medicinal chemistry. Structural mimetics of α-helices, β-turns or β-strands could maintain or restore biological functions and should possess biological activity. At this time, the most challenging classes of PPIs are those mediated by β-sheet interactions, which are implicated in a number of diseases. Only a few β-strand mimics have been published to date. This study presents an evaluation of oligothienylpyridyl scaffolds in view of their ability for β-strand mimicry. In this study, theoretical ring twist angle predictions for these scaffolds have been validated by X-ray diffraction and molecular dynamics simulations with NMR constraints. Careful choice of substituent and heavy-atom positions in the foldamer units opens the way to produce reasonably coplanar compounds mimicking β-strand side-chain distribution.