| 1. |
- Nyholm, Per-Georg, 1958, et al.
(författare)
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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.
- 2009
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Ingår i: J Comput Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 23:12, s. 845-852
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Tidskriftsartikel (refereegranskat)abstract
- Abstract 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]α1-3Gal 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 Fucα1-2Gal 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.
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| 2. |
- Nyholm, Per-Georg, 1958, et al.
(författare)
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The use of a genetic algorithm search for molecular mechanics (MM3)-based conformational analysis of oligosaccharides.
- 2005
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Ingår i: Carbohydrate Research. - : Elsevier BV. - 0008-6215 .- 1873-426X. ; 340:5, s. 1059-1064
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Tidskriftsartikel (refereegranskat)abstract
- We have implemented a system called glygal that can perform conformational searches on oligosaccharides using several different genetic algorithm (GA) search methods. The searches are performed in the torsion angle conformational space, considering both the primary glycosidic linkages as well as the pendant groups (C-5–C-6 and hydroxyl groups) where energy calculations are performed using the MM3(96) force field. The system includes a graphical user interface for setting calculation parameters and incorporates a 3D molecular viewer. The system was tested using dozens of structures and we present two case studies for two previously investigated O-specific oligosaccharides of the Shigella dysenteriae type 2 and 4. The results obtained using glygal show a significant reduction in the number of structures that need to be sampled in order to find the best conformation, as compared to filtered systematic search.
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| 3. |
- Strino, Francesco, 1980
(författare)
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Computational analysis of oligosaccharide conformations – methodological development, applied studies, and design of glycomimetics
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Carbohydrates are the most abundant class of biomolecules. Besides their roles as structural elements and energy storage, they are involved in signaling and recognition processes. Their functions and activities depend on their preferred conformations. The software GLYGAL was developed to perform conformational studies of oligosaccharides using a genetic algorithm tailored for carbohydrates. The new method was applied to the highly branched exopolysaccharide of Burkholderia cepacia. The results show that its heptasaccharide repeating units assume a well defined conformation, stabilized by steric interactions between consecutive units. Furthermore, GLYGAL was used to calculate favorable conformations of histo-blood group antigens. The compounds were then fitted in the binding site of the surface protein of the norovirus VA387 strain and their binding affinity was estimated by molecular dynamics and Glide scoring, giving insights into the interaction patterns involved in norovirus infection. Finally, the mimetic properties of thioglycosidic and selenoglycosidic derivatives of the ABH antigens were studied by conformational and dockings studies, indicating potentially bioactive derivatives with increased resistance to hydrolysis. In conclusion, the computational methodologies developed during this study were successfully used, together with existing methods, for the investigation of natural carbohydrates and the rational design of glycomimetics.
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| 4. |
- Strino, Francesco, 1980, et al.
(författare)
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Conformation of the exopolysaccharide of Burkholderia cepacia predicted with molecular mechanics (MM3) using genetic algorithm search.
- 2005
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Ingår i: Carbohydrate Research. - : Elsevier BV. - 0008-6215 .- 1873-426X. ; 340:5, s. 1019-1024
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Tidskriftsartikel (refereegranskat)abstract
- We present a computational conformational analysis of the exopolysaccharide of Burkholderia cepacia, which is believed to play a role in colonization and persistence of B. cepacia in the lungs of cystic fibrosis patients. The repeating unit of the exopolysaccharide is a heptasaccharide with three branches, which cause significant steric restraints. Conformational searches using glygal, an in-house developed software using genetic algorithm search methods, were performed on fragments as well as on the complete repeating unit with wrap-over residues. The force field used for the calculations was MM3(96). The search showed four favored conformations for an isolated repeating unit. However, for a sequence of several repeating units, the calculations indicate a single, well-defined linear conformation.
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