Rational drug design of conformationally defined ligands
Proteins with concave binding pockets are difficult to target with small, drug-like molecules. We achieved our most promising ligands by a rational design of ligands with a defined 3D-conformation (Wang et al., Bischoff et al, Pomplun et al). For this approach it is essential to have rapid access to high quality structural information on the binding mode and bioactive conformation of the protein ligands.
For FKBP51, our most promising protein target, we obtained a chemical stating point from the naturally occurring product FK506. Based on cocrystallographic data, the initally complex FK506 scaffold could be truncated and simplified substantially.
The knowledge of the binding mode allowed us to introduce a strategically place linker that stabilized the active conformation. Finally, a stereochemically defined extension of the rigidified scaffold substantially reduced the binding affinity for FKBP51.