New Perspective on How and Why Immunophilin FK506-Related Ligands Work

We report on theoretical and experimental data that help elucidate the intimate structural and thermodynamical cooperative mechanisms that are responsible for the inhibitory activity of FK506-related ligands of the FKBP12 protein, a cytosolic enzyme that catalyzes the cis–trans isomerization of prolyl amide bonds and that is involved in immunosuppression and neuronal functioning. Effective FKBP12 ligands are those that mimic in bulk solution the structure of the Tacrolimus natural drug with respect to (i) the orientation of the two carbonyl groups units of the ligand that will form, upon binding, H-bonds with specific residues in the protein binding pocket and (ii) the reduced conformational entropy as in the rigid macrolide Tacrolimus. On this basis, we have rationally designed in silico and synthesized a new compound, Elte421, as a simple variant of an existing FK506-related ligand. The experimental characterization of the synthesized compound via fluorescence quenching shows that Elte421 has a binding affinity for human FKBP12 comparable to that of FK506 natural drug.