title: Fragment-based synthesis and SAR of modified FKBP ligands: influence of different linking on binding affinity.
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.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, University of Leiden, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Röhrig
authors.forename: Caroline
authors.initials: C
authors.lastname: Loch
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Guan
authors.forename: Gregg
authors.initials: G
authors.lastname: Siegal
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: 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*
chemical_list: D008024:Ligands; D022021:Tacrolimus Binding Proteins