Augmented reversible photoswitching of drug-target interaction through "surface borrowing"

Reversibly switching bioactive molecules by light could allow spatiotemporal control of their biological functions, but designing such drug molecules with large functional differences between two light-switchable states remains difficult. We extend the concept of "borrowing protein" to "borrowing surface" for the design of photo-switchable molecules. By using an azobenzene conjugated cyclosporin derivative as a model system we have demonstrated that the enhanced steric hindrance resulting from this "borrowing surface" design can cause augmentation of the functional difference between the cis and trans conformers of this light-switchable compound. Interestingly, not only near UV light of 366nm but also visible light of 430nm or 525nm can induce efficient photoswitching of the interactions between the light-responsive ligand and target protein. Additionally, by using molecular modeling and docking techniques we obtained structural insights into the switchable protein-ligand interaction, illustrating the effect of steric hindrance associated with the borrowing surface design.