The modelling of species with potential use as carriers of radionuclides for bone cancer therapy
| dc.contributor.author | Robinson, Janine | |
| dc.date.accessioned | 2009-04-01T11:08:09Z | |
| dc.date.available | 2009-04-01T11:08:09Z | |
| dc.date.issued | 2009-04-01T11:08:09Z | |
| dc.description.abstract | The ability of the Generalised AMBER Force Field (GAFF) to model the structure of bisphosphonate ligands, C(R1)(R2)(PO3 2-)2, important compounds in the treatment of bone cancer, by molecular mechanics methods is evaluated. The structures of fifty bisphosphonates and nine bisphosphonate esters were predicted and compared with their crystal structures. Partial charges were assigned from a RHF/6-31G* single point calculation at the geometry of the crystal structure. Additional parameters required for GAFF were determined using the methods of the force field’s developers. The structures were found to be well replicated with virtually all bond lengths reproduced to within 0.015 Å (1.2s). Bond angles were reproduced to within 1.9o (0.8s). The observed gauche or anti conformation of the molecules was reproduced, although in several instances gauche conformations observed in the solid state energy-minimised into anti conformations, and vice versa. The interaction of MDP (R1 = R2 = H), HEDP (R1 = OH, R2 = CH3), APD (R1 = OH, R2 = (CH2)2NH3 +), alendronate (R1 = OH, R2 = (CH2)3NH3 +) and neridronate (R1 = OH, R2 = (CH2)5NH3 +) with the (001), (010) and (100) faces of hydroxyapatite was examined by energy-minimising twenty random orientations of each ligand 20 Å from the mineral and then at about 8 Å from the surface whereupon the ligand relaxes onto the surface. The difference in energy between the two systems is the interaction energy. In all cases interaction with hydroxyapatite caused a decrease in energy. On the (001) face, both phosphonate groups interact near a surface Ca2+ ion. The magnitude of the exothermic interaction energy varies with molecular volume (MDP < HEDP < APD < alendronate) except for neridronate, which interacts less effectively than alendronate because the long amino side chain folds in on itself and does not align with the surface of the mineral. The bisphosphonates adopt two conformations on the (010) face. In the first of these, found for MDP and 40% of the alendronate structures, both phosphonates interact with the surface and the side chain points away from the surface. In the second conformation, one phosphonate and the Ca side chain interact with the surface. The interaction energy increases with the molecular volume of the ligand, again with the exception of neridronate. Two conformations also occur on the (100) face. In the first conformation, only one of the phosphonate groups points towards the surface and the Ca side chain interacts with the surface; in the second conformation the Ca side chain interacts strongly with the surface and both phosphonate groups point away from the surface towards the solution. The first conformation is energetically more favourable. Its magnitude is virtually insensitive to the nature of the side chain and is similar to the magnitude of the interaction energy on the other two faces. The magnitude of the second conformation increases with the size of the Ca side chain. | en |
| dc.identifier.uri | http://hdl.handle.net/10539/6858 | |
| dc.language.iso | en | en |
| dc.title | The modelling of species with potential use as carriers of radionuclides for bone cancer therapy | en |
| dc.type | Thesis | en |