Novel sulfonamides for the treatment of breast and cervical cancers
Permanent link to Research Commons versionhttps://hdl.handle.net/10289/15005
A series of novel sulfonamides were studied computationally to identify a potential mechanism of action for the treatment of breast and cervical cancers. Previous in vivo testing demonstrated varying degrees of effectiveness, with seven molecules showing the highest cytotoxicity. Computational calculations were chosen as the means for determining the drug target. Previous studies indicated β-Tubulin and Carbonic Anhydrase IX as the most likely proteins of interest, so these were selected for study. The computational methodology selected for this study follows that of Krzywik et al.¹ For this, conventional docking studies were undertaken using Autodock Vina, followed by more accurate and computationally demanding molecular dynamics simulations using the MM/PBSA procedures in AMBER. Docking studies for the seven active compounds were performed using Vina, and showed promising results. The three most effective compounds (5AP, 6AP and 7BP) were then utilised in a series of MM/PBSA calculations to determine strength of interaction between the sulfonamides and drug targets. The results of the AMBER calculations determined β-Tubulin to be the more likely drug target, although this result did show 6AP (the most effective in vivo molecule) to have the weakest binding, which was an unexpected result. A LIGPLOT study was done to determine a potential cause for this, showing a heavy emphasis on non-polar interactions between the drug molecules and proteins. Drug-like comparisons and pKa calculations were also performed, showing all three molecules to have very similar acidity and hydrogen bond capabilities, but suggesting lipophilicity and molecule size to be possible determining factors in the overall effect of the compounds. Transport across the cell membrane and through the cytoplasm were also suggested as potential reasons for the differing results, and further studies into these were suggested for possible confirmation.
The University of Waikato
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- Masters Degree Theses