Defining a Simplified Pharmacophore for Simocyclinone D8 Inhibition of DNA Gyrase

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Gaskell, Lauren
Simocyclinone D8; DNA Gyrase; Medicine and Health Sciences; Pharmacy and Pharmaceutical Sciences
thesis / dissertation description
The type II topoisomerase subfamily of enzymes has been clinically targeted by the widely used, broad-spectrum quinolone class of antibacterials. Due to emerging drug-resistant strains of bacteria, the quinolones’ effectiveness is threatened. The natural product simocyclinone D8 (SD8) has shown the ability to inhibit the type II topoisomerase, DNA gyrase, even when mutated to be resistant to the quinolones. In order to determine the pharmacophore required for SD8 binding to DNA gyrase, 16 compounds were synthesized. These compounds were then tested by surface plasmon resonance for their ability to inhibit the DNA – DNA gyrase binding interaction. It was found that three compounds were able to inhibit the DNA – DNA gyrase binding interaction, while another showed partial inhibition of the interaction. From this data, a minimum pharmacophore was able to be determined. The pharmacophore required a coumarin scaffold bonded to a carboxylic acid group through an approximately 15 Å hydrocarbon linker. Functional supercoiling assays determined that while the compounds were able to bind the enzyme, the binding did not inhibit DNA gyrase’s ability to supercoil DNA.