I. Development of sulfonyl piperazine LpxH inhibitors against multi-drug resistant Gram-negative bacteria II. Exploration towards new TRPM8 agonists for dry eye disease

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2023

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Abstract

The discovery of new drug scaffolds is a time-consuming and costly process. As new technologies are developed and implemented into the drug discovery process, these costs are being lessened. Of these methods, computer-aided drug discovery is the most widely implemented as it reduces the number of compounds that need to be explored synthetically. Computer-aided drug discovery has also become a powerful tool as it envelops a wide range of computational methods that can be used to identify or optimize lead compounds for various disease states or drug targets.The first part of the dissertation presents the design, synthesis, and biological evaluation of sulfonyl piperazine LpxH inhibitors. The emergence of widespread antibiotic resistance among Gram-negative pathogens has led to an urgent need for a new class of antibiotics to fight multidrug-resistant Gram-negative bacteria. Lipid A is a critical component of lipopolysaccharides present on the outer membrane of Gram-negative bacteria that prevents penetration of the membrane by external detergents and antibiotics. The biosynthesis of lipid A occurs through the Raetz pathway via 9 distinct enzymes, one of which is known as LpxH. The dual mechanism of cell killing due to the inhibition of LpxH and its presence in the majority of Gram-negative bacteria makes it an attractive target for novel antibiotics. Based on the structure of AZ1, a small molecule inhibitor of LpxH identified by AstraZeneca, we have synthesized and evaluated a series of sulfonyl piperazine LpxH inhibitors. Our study allowed for the establishment of a comprehensive structure-activity relationship of the various components of AZ1. We also obtained the first crystal structure of Klebsiella pneumoniae LpxH in complex with a sulfonyl piperazine LpxH inhibitor which illuminated how this class of LpxH inhibitors fits into the binding pocket of LpxH and guided the design of inhibitors with increased potency. Our findings will be instrumental in the discovery of new antibiotics against multidrug-resistant Gram-negative pathogens. The second part of the dissertation describes the modification of existing TRPM8 ligands and the search for alternative scaffolds towards the development of a new TRPM8 agonist for the treatment of dry eye disease. As the use of technology continues to increase, so does the incidence of dry eye disease, especially in younger individuals. Modulation of the transient receptor potential cation channel TRPM8 has been implicated as a route for the treatment of dry eye disease as TRPM8 plays a critical role in basal tear production, eye blinking, and is the sensor for eye dryness. Current well-known modulators of TRPM8 such as menthol, icilin, and WS-12, are not suitable for ocular use as they have undesirable physical properties and have off-target effects on other transient receptor potential channels. The recently discovered small molecule cryosim-3 which was identified as a TRPM8 specific agonist provides a good starting point for the development of a new agonist suitable for ocular studies. Through the use of cryo-electron microscopy, molecular docking, and virtual screening, we have begun to understand the different binding orientations of various TRPM8 ligands. This information has aided us in probing new chemical space for the identification of a TRPM8 agonist with improved potency, selectivity, and physical properties over existing agonists.

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Ennis, Amanda (2023). I. Development of sulfonyl piperazine LpxH inhibitors against multi-drug resistant Gram-negative bacteria II. Exploration towards new TRPM8 agonists for dry eye disease. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/29205.

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