Rational design strategies for innovative small-molecule scaffolds inspired by three pivotal protein secondary structures

Abstract

We developed a design strategy focusing on pivotal secondary structural motifs—α-helix, β-strand, and β-turn—critical for PPI recognition, using a common core skeleton. The resulting peptide-inspired pyrimidodiazepine scaffolds were further subjected to comprehensive phenotypic screening to evaluate their efficacy. Our strategy offers a transformative approach to developing small-molecule PPI modulators with broad therapeutic potential.