Design, synthesis, FGF-1 binding, and molecular modeling studies of conformationally flexible heparin mimetic disaccharides.
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.
Liu
Ligong
L
Drug Design Group, Progen Pharmaceuticals Limited, PO Box 2403, Toowong, Brisbane, Qld 4066, Australia.
Bytheway
Ian
I
Karoli
Tomislav
T
Fairweather
Jon K
JK
Cochran
Siska
S
Li
Caiping
C
Ferro
Vito
V
D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002236:Carbohydrate Conformation; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D013816:Thermodynamics; D014994:Xylose / Q000737:chemistry
D004187:Disaccharides; D016220:Fibroblast Growth Factor 1; D006493:Heparin; D014994:Xylose; D005947:Glucose