Contemplating 1,2,4-Thiadiazole-Inspired Cyclic Peptide Mimics: A Computational Investigation.

Marine derived cyclic peptides have inspired chemists for decades as the cavitand architecture can be compared with macrocyclic ligands, and hence easily conceived as mediators of metal-ion transport. Lissoclinamide 5 and ascidiacyclamide are two such cyclic peptides that have received much attention both for their metal ion complexation properties and biological activity; the metal ion binding properties of mimics of these two systems have been reported. Reported herein is a computational study aimed at evaluating the stability, and potential for copper(ii) ion binding by lissoclinamide 5 mimics that substitute the naturally occurring 4-carboxy-1,3-thiazole units for novel valine- and phenylalanine-derived 1,2,4-thiadiazole units. Our results suggest that one lissoclinamide 5 mimic, 1,2,4-thiadiazole (TDA)-lissoclinamide 9 , may be capable of forming a complex with one Cu^II ion, [Cu(9 -H)(H₂O)]⁺. A complex with two Cu^II ions, [Cu₂(9 -H)(μ-OH)]²⁺, was also considered. These results set the stage for synthetic and experimental metal binding studies. 1,2,4-Thiadiazole-lissoclinamide 9 , a next generation mimic design, was evaluated in silico for metal binding aptitude towards Cu^II ions. DFT calculations suggest that TDA-lissoclinamide may be capable of forming a complex with one Cu^II ion, [Cu(9 -H)(H₂O)]⁺. These results underpin future synthetic and experimental metal binding studies. [ABSTRACT FROM AUTHOR]