Affiliation:
1. ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP) Institute for Photonics and Advanced Sensing (IPAS) Department of Chemistry The University of Adelaide North Terrace Adelaide SA 5005 Australia
2. Guangxi Key Laboratory of Electrochemical and Magneto-chemical Functional Materials College of Chemistry and Bioengineering Guilin University of Technology Guilin 541004 P. R. China
Abstract
AbstractThe 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 more than fivefold difference in inhibitory activity between isomeric states, whereas the best small‐molecule inhibitor only showed a 3.4‐fold difference. Docking and molecular modelling suggest this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation; this 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.
Funder
Australian Research Council
Australian National Fabrication Facility
Subject
Organic Chemistry,Molecular Biology,Molecular Medicine,Biochemistry