Conformational analysis of thioglycoside derivatives of histo-blood group ABH antigens using an ab initio-derived reparameterization of MM4: implications for design of non-hydrolysable mimetics.
Histo-blood group ABH antigens serve as recognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor progression. Thus, they are of interest as a starting point for drug design. In this respect, potent non-hydrolysable derivatives such as thioglycosides are of special interest. As prerequisite to enable estimations of ligand properties relative to their natural counterparts, conformational properties of the thioglycosidic derivatives of ABH trisaccharides and their disaccharide units were calculated using systematic and filtered systematic searches with the MM4 force field. Parameters for the glycosidic torsions of thioglycosides were independently derived from ab initio calculations. The resulting energy deviations required a reparameterization of MM4 to a new parameter set called MM4R. The data sets obtained using MM4R reveal that the thioglycosides have somewhat increased levels of flexibility about the major low-energy conformations shared with the corresponding O-glycosides. In the trisaccharides, the thiosubstitution of the Gal[NAc]alpha1-3Gal linkage leads to a preference for a conformation which is the secondary minimum of the natural counterparts. This conformation also generates contacts between the N-acetyl group and the fucose moiety in the blood group A derivative. Calculations further indicate that thiosubstitution of only the Fucalpha1-2Gal linkage does not affect the conformational preferences compared to the natural trisaccharide. Thiosubstitution of both linkages in the trisaccharide results in increased flexibility but the favored conformation of the natural trisaccharides is preferred. The study suggests that thioglycoside derivatives of ABH antigens could have pharmaceutical interest as ligands of lectins and other carbohydrate-binding proteins.
Strino
Francesco
F
Institute of Biomedicine/Section of Medical Biochemistry, Göteborg University, 40530 Göteborg, Sweden.
Lii
Jenn-Huei
JH
Gabius
Hans-Joachim
HJ
Nyholm
Per-Georg
PG
D032701:Biomimetics; D001789:Blood Group Antigens / Q000737:chemistry*; D004187:Disaccharides / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D013865:Thioglycosides / Q000737:chemistry*; D014312:Trisaccharides / Q000737:chemistry
D001789:Blood Group Antigens; D004187:Disaccharides; D013865:Thioglycosides; D014312:Trisaccharides