From Conformational Control to GPCR Recognition: Structure-Guided Design of Short Peptide and Peptidomimetic Ligands

G protein-coupled receptors (GPCRs) remain among the most important drug targets, yet the rational design of short peptide and peptidomimetic ligands is complicated by a central problem: the same conformational flexibility that enables molecular recognition can also reduce selectivity and obscure the bioactive geometry. We therefore explore conformational control as a practical bridge between peptide structural chemistry and GPCR-focused ligand design.

Our approach combines experimental structural information with computational analysis of receptor recognition. Short peptide-derived scaffolds with different degrees of conformational restriction were examined using single-crystal X-ray diffraction and conformational analysis, followed by molecular docking and molecular dynamics in selected GPCR binding pockets. Particular attention was given to pseudo-cyclization, sterically restricted residues, and fluorinated termini as strategies for preorganizing the ligand and modulating the presentation of recognition groups.

Across representative systems, conformational restriction reduced the accessible structural space without eliminating local adaptability. In a CF₃-containing dipeptidomimetic, crystal-derived interaction patterns were compared with first-shell environments sampled in the β₂-adrenergic, dopamine D3, and serotonin 5-HT2A receptors. The receptor models showed that the same substituent can encounter distinct aliphatic, aromatic, and polar microenvironments, emphasizing that useful preorganization must coexist with receptor-dependent adaptation.

These results support a design principle in which short peptide GPCR ligands are treated neither as rigid small molecules nor as unconstrained peptides. Instead, controlled flexibility and experimentally informed preorganization may provide a more rational starting point for developing compact peptide-based GPCR modulators.