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Molecular modeling of heparanase and heparanase-binding oligosaccharides

Molecular modeling studies on putative heparanase substrates and inhibitors were made. The results enabled both detailed description of 3D structures of these compounds for the first time and estimation of the influence of the factors (counter-ions and substituents) that affect their conformations. These data are important for understanding the intermolecular interactions of the compounds with the target protein heparanase at the molecular level and were used in modelling of these interactions. Results of molecular mechanics calculations can be divided in several groups according to the type of compounds analyzed:
- Heparin/HS oligosaccharides;
- Maltohexaose sulfates;
- K5-derived polysulfates;
- Other saccharides with various sulfation pattern.

Both quantum chemical and molecular mechanics calculations showed that counter-ions play an important role in stabilization of the 3D structure of sulfated oligosaccharides. Structures of all analyzed saccharides were affected by the coordination of Na+ ions between the -NSO3 and the -COO groups.

Especially in larger oligomers, pentasaccharides and hexasaccharides, conformations at the glycosidic linkages were influenced by charge-charge interactions, by interactions between the COO- and the (OH) groups and between the -NSO3 and the -2-OSO3 groups. The sulfate groups showed considerable effect upon 3D structures especially in 2,6-sulfated (or in 2,3,6-sulfated) compounds. Their linkage conformations were different with non-substituted compounds or with 6-sulfated derivatives. Quantum chemical calculations also enabled description of the character chemical bonds bond, charges, etc.

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Institute of Chemistry, Slovak Academy of Sciences
Dubravska cesta 9
84538 Bratislava
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