G protein-coupled receptors (GPCRs) are central to many therapeutic areas, but their conformational flexibility—favoring a basal state—makes agonist discovery challenging. To address this, we developed peptidomimetics that mimic the α5 helix of G proteins, effectively stabilizing the active conformations of β2-adrenergic (β2AR) and dopamine D1 (D1R) receptors. These molecules enabled the identification of agonist-like fragments during fragment-based screening, serving as valuable tools for early-stage drug discovery. We further extended this approach to design Gq mimetics using the same strategy. These peptidomimetics also hold promise for structural biology studies of GPCRs.