Supramolecular assembly of novel achatin structurally similar peptide as potential G protein-coupled receptors anticancer ligands: focus on its pseudo-macrocycle nature.

This study presents the synthesis and comprehensive characterization of a novel, modified ultra-short peptide, Ac-Phe-Aib-Deg-OH (N-acetyl-L-phenylalanyl-α-aminoisobutyryl-α,α-diethylglycine), (1), highlighting its potential as an anticancer ligand for G protein-coupled receptors (GPCRs). The structure of the compound was elucidated using single-crystal X-ray crystallography, revealing its pseudo-macrocyclic nature. Hydrogen bonds and dispersion forces drive the hierarchical supramolecular self-assembly of (1). A comparative analysis with structurally similar structures, that is, achatin derived from the Cambridge Structural Database, was conducted using diverse in silico methods. A detailed analysis of intra- and intermolecular interactions in the structures, especially using modern structural database-driven techniques, provides further insight into the preferential bonding mode of (1) as a potential drug candidate. Density functional theory calculations were performed to rationalize the interactions and reactivity of the molecules. To validate the predicted anticancer activity of the analysed molecules, we evaluated the binding affinities of these molecules to cancer-related GPCRs. We examined the interaction maps using molecular docking analysis with targets associated with various types of cancer. These findings suggest that (1) could be a promising candidate for future studies on designing innovative pseudo-macrocyclic ultra-short peptides containing unnatural amino acids for new targeted anticancer therapy.