title: Augmented reversible photoswitching of drug-target interaction through "surface borrowing".
abstract: 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.
authors.affiliation: Institute for Pharmacy, Department of Pharmacology, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany. Electronic address: frank.erdmann@pharmazie.uni-halle.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Erdmann
authors.affiliation: B CUBE Center for Molecular Bioengineering, Technical University Dresden, Arnoldstr. 18, 01307 Dresden, Germany.
authors.forename: Weilin
authors.initials: W
authors.lastname: Lin
authors.affiliation: Institute for Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Charlott
authors.initials: C
authors.lastname: Platzer
authors.affiliation: Institute for Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Institute for Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Max-Planck-Institute for Biophysical Chemistry, Göttingen, BO Halle (Saale) Weinbergweg 22, 06120 Halle (Saale), Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.affiliation: B CUBE Center for Molecular Bioengineering, Technical University Dresden, Arnoldstr. 18, 01307 Dresden, Germany. Electronic address: yixin.zhang@bcube-dresden.de.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D062105:Molecular Docking Simulation; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013499:Surface Properties; D014466:Ultraviolet Rays
chemical_list: D004364:Pharmaceutical Preparations
keywords: Calcineurin; Ciclosporin; CsA; Immunosuppression; Light-switchable drug