This project comprises the rational design and synthesis of natural product-derived macrocycles as improved subtype-selective ligands for FKBP51, a validated drug for depression, obesity and chronic pain.

First, the students will synthesize a common core unit following internally established routes. Second, they will synthesize optically pure building blocks, which are then used to elaborate the core unit in a combinatorial fashion. All synthesized compounds will be characterized by NMR, MS and HPLC, their in vitro binding affinities will be determined in biochemical fluorescence polarization and nanoBRET assays, and for advanced compounds the binding mode will be established by X-ray crystallography of FKBP51 complexes.