Barata, Teresa Silva; (2011) Structural studies on glycosylated polyamidoamine dendrimers. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Polyamidoamine (PAMAM) dendrimers are hyper-branched molecules. Glucosamine conjugates of generation 3.5 PAMAM dendrimers have been reported to have immunomodulatory and antiangiogenic activity by preventing the LPS (lipopolyssacharide) triggered inflammatory response. These conjugates are prepared by a divergent synthetic route and the saccharide loading on dendrimer end groups has been estimated experimentally. The position and the distribution of the conjugated saccharides is varied and cannot be determined. Hence it is not possible to determine detailed structure activity correlations. Using computational strategies, the aim of these studies is to understand the structural features of glycosylated dendrimers that contribute to their activity and identify the interactions of these dendrimers with the biological target. The overall goal is to use the increased insight about the possible mode of action of the glucosamine PAMAM conjugates to aid the design of more potent dendrimer derivatives. A method was first developed to allow the in silico generation of 3D models of the modified dendrimers. The electronic properties of these molecules were studied and the Frontier Molecular Orbital theory was used to understand the reactivity involved with saccharide loading and distribution on the modified dendrimer's surface. Conformational flexibility and the potential availability of the sugars for possible interactions with the biological target were then studied by the molecular dynamics of fully solvated molecules. Molecular properties were estimated for all generated structures. The representative conformations of flexible glycosylated dendrimers were used in rigid docking studies with the protein called MD-2, which is a component of the LPS recognition system. The docking studies were followed by dynamic simulations of the glycosylated dendrimer with MD-2. Based on these studies, a mechanism of action for glycosylated PAMAM dendrimers has been proposed where the dendrimer glucosamine conjugate interacts with MD-2 at the opening of the cavity and thus prevents LPS binding. This work demonstrates how molecular modelling techniques can be used to elucidate the structural features of dendrimeric structures and their interaction with biological targets. In this specific case, the knowledge gained about the structural features of glycosylated dendrimers allowed the establishment of a set of criteria to distinguish between active and inactive dendrimers and enabled the rational design of biological active hybrid molecules. This methodology has the potential to be expanded to the development of novel polymeric molecules towards specific biological targets.

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