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Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity
Author(s) -
Röhrig Christoph H.,
Loch Caroline,
Guan JiaYing,
Siegal Gregg,
Overhand Mark
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600296
Subject(s) - fkbp , chemistry , linker , docking (animal) , drug discovery , stereochemistry , combinatorial chemistry , oxime , ligand (biochemistry) , target protein , thioester , biochemistry , enzyme , receptor , medicine , nursing , computer science , gene , operating system
Abstract 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.