Exploring Photoswitchable Binding Interactions with Small Molecule- and Peptide-Based Inhibitors of Trypsin

Abstract

The ability to photochemically activate a drug, both when and where needed, requires optimisation of the difference in biological activity between each isomeric state. As a step to this goal, we report small molecule and peptide-based inhibitors of the same protease - trypsin - to better understand how photoswitchable drugs interact with their biological target. The best peptidic inhibitor displayed a >5-fold difference in inhibitory activity between isomeric states, whereas the best small molecule inhibitor only showed a 3.4-fold difference. Docking and molecular modelling suggests this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation, which is not observed for the small molecule inhibitor. Hence, we demonstrate that significant structural changes in critical binding motifs upon irradiation are essential for maximising the difference in biological activity between isomeric states. This is an important consideration in the design of future photoswitchable drugs for clinical applications.