Design, synthesis, FGF-1 binding, and molecular modeling studies of conformationally flexible heparin mimetic disaccharides |
| |
Authors: | Liu Ligong Bytheway Ian Karoli Tomislav Fairweather Jon K Cochran Siska Li Caiping Ferro Vito |
| |
Institution: | Drug Design Group, Progen Pharmaceuticals Limited, PO Box 2403, Toowong, Brisbane, Qld 4066, Australia. |
| |
Abstract: | Disaccharide mimetics of a heparin sequence that binds to fibroblast growth factors were prepared by coupling a D-galactose donor with a methyl beta-D-gluco- or xylopyranoside acceptor. When fully sulfated, the glucose or xylose moieties exist in solution in equilibrium between the (4)C1 and (1)C4 conformers, as confirmed by 1H NMR spectroscopy, thus mimicking the conformationally flexible L-iduronic acid found in heparin. Docking calculations showed that the predicted locations of disaccharide sulfo groups in the binding site of FGF-1 are consistent with the positions observed for co-crystallized heparin-derived oligosaccharides. Predicted binding affinities are in accord with experimental Kd values obtained from binding assays and are similar to the predicted values for a model heparin disaccharide. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|