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 Francesco Strino Æ Jenn-Huei Lii Æ Hans-Joachim Gabius Æ Per-Georg Nyholm Received: 14 July 2009 / Accepted: 31 August 2009 / Published online: 15 September 2009 Ó Springer Science+Business Media B.V. 2009 Abstract Histo-blood group ABH antigens serve as rec- ognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor pro- gression. 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 tri- saccharides 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 flexi- bility about the major low-energy conformations shared with the corresponding O-glycosides. In the trisaccharides, the thiosubstitution of the Gal[NAc]a1-3Gal 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. Calcula- tions further indicate that thiosubstitution of only the Fuca1-2Gal linkage does not affect the conformational preferences compared to the natural trisaccharide. Thio- substitution 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. Keywords Blood group antigens Á Drug design Á Lectins Á Molecular mechanics Á Thioglycoside Introduction The ABH family of histo-blood group antigens was origi- nally defined in transfusion medicine, where incompatibility results in severe complications [1]. The search for reagents, which reliably distinguish between these epitopes on erythrocytes in clinical practice, prompted systematic screening of plant extracts. This work—together with applying the H-specific eel serum and sugars as inhibitors of lectin-dependent hemagglutination—led to the identifica- tion of the carbohydrate nature of the ABH blood group substances [2, 3]. Binding of these determinants by proteins is not limited to the mentioned laboratory tools and serum antibodies. Of medical relevance, bacteria and viruses as well as normal and tumor cells can bind to the tri- and tet- rasaccharide determinants [4–7]. In lung cancer this inter- action has prognostic relevance [8]. Evidently, these glycans are important bioactive ligands on the cell surface [9]. This F. Strino Á P.-G. Nyholm (&) Institute of Biomedicine/Section of Medical Biochemistry, Go ¨teborg University, Medicinaregatan 9, 40530 Go ¨teborg, Sweden e-mail: nyholm@medkem.gu.se; per-georg.nyholm@medkem.gu.se J.-H. Lii Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan H.-J. Gabius Institut fu ¨r Physiologische Chemie, Tiera ¨rztliche Fakulta ¨t, Ludwig-Maximilians-Universita ¨t Mu ¨nchen, Veterina ¨rstr. 13, 80539 Mu ¨nchen, Germany 123 J Comput Aided Mol Des (2009) 23:845–852 DOI 10.1007/s10822-009-9301-4