Fragment-based synthesis and SAR of modified FKBP ligands: influence of different linking on binding affinity.
The viability of the fragment-based approach for lead discovery depends on reliable fragment-screening methods combined with straightforward fragment-linking- or fragment-growing-chemistry. In the present study we sought a flexible synthetic approach that would allow efficient synthesis of a variety of linkers that can subsequently be tested for biological activity. We applied this approach to fragments known to bind to FKBP12 (FK506 binding protein), a peptidyl-prolyl isomerase involved in immunosuppression and neural functioning. In our set of linked FKBP ligands, ester and thioester linkages resulted in high-affinity ligands, whereas an amide linkage decreased affinity remarkably; oxime and triazole linkages were not tolerated by the target protein's binding pocket, rendering these ligands ineffective. By investigating corresponding derivatized non-linked fragments and docking studies of linked fragments, we were able to evaluate the effect of the linker region on ligand binding affinity.
Röhrig
Christoph H
CH
Leiden Institute of Chemistry, Gorlaeus Laboratories, University of Leiden, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Loch
Caroline
C
Guan
Jia-Ying
JY
Siegal
Gregg
G
Overhand
Mark
M
D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D022021:Tacrolimus Binding Proteins