Characterizing new conotoxin interactions with G protein-coupled receptors by using PRESTO-Tango

Conotoxins constitute an extensive natural library of marine drug candidates. Their structural uniqueness enables these peptides to bind to a variety of receptors, transporters, and enzymes with high selectivity. For cone snails, this means a powerful hunting tool, for scientists; conotoxins can be used as valuable research and diagnostic tools, as well as drug candidates. In this study, several conotoxins were tested to determine whether they bind to G-protein-coupled receptors, laying the foundation for future research. The involvement of G-protein-coupled receptors in numerous major physiological and pathological signal pathways highlights their potential as drug targets. Using AlphaFold2, potential interactions between conotoxins and G-protein-coupled receptors were generated and these were subsequently validated in a cell-based receptor activity assay. Of 25 tested interactions, two conotoxins may have induced receptor activity, and therefore potentially bound to the receptor. The results indicate that AlphaFold2's predictions help identify potential peptide-receptor interactions; however, more conotoxin-receptor interactions need to be studied, and any potential findings should be verified through binding or different activation-based assays.