Structures of Metal Based Non-Steroidal Anti-Inflammatory Drugs
School of Chemistry
University of Tasmania
Biochemical Veterinary Research
h03 - PC
|Biochemical Veterinary Research holds patents on and successfully markets, both nationally and internationally, a range of veterinary products based on metal indomethacin complexes. These metal dimer complexes are more active and less toxic than the parent non-steroidal anti-inflammatory drugs (NSAID). Despite extensive collaborative research programmes and successful marketing strategies, the critical question of how metal-based NSAIDs work remains unanswered. This theoretical computational chemistry project aims to provide additional molecular information, including minimum energy optimised conformations, charge distributions, molecular polarities, bond lengths and angles, to supplement extensive data from other research programmes for characterising the bio-transformation products of metal indomethacin.|
What are the results to date and the future of the work ?
Suggestions have been made in the literature that the least destructive decomposition pathway of metal indomethacin complexes might involve exchange of a ligand at the site which controls complex solubility and possibly transport of the metal complex across cell membranes. It is also possible that the metal complex might decompose to produce monomeric metal indomethacin species or the dimer species might aggregate to larger species in solution. For BVR, it is important to establish to what extent and at what stage these processes occur, not only from the point of view of establishing biotransformation products, but also to establish why the metal-NSAID complexes are so much less toxic than the un-complexed NSAIDs. Such information is also a requirement for international registration. A range of monomeric commercial NSAID species has been investigated to date. These include Indomethacin, Diclofenac, Ibuprofen, Indobufen, Naproxen, Sulindac, and Surgam.
What computational techniques are used ?
Gaussian 94 ab initio calculations are being used to generate these molecular parameters. Preliminary gas phase calculations are being done at the RHF/3-21G level. These are then followed by frequency analyses and full geometry optimisations in an aqueous environment at the RHF/6-31G and RHF/6-31G(d) levels of theory. Outputs from these are presently being prepared for final geometry optimisations at the MP2/6-31g(d) level.
Appendix B -