Study of protein-macrocycle Interactions for lessons in drug design
Villar, Elizabeth A.
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Macrocycles (MCs) have become an increasing area of interest for drug design efforts, especially for classically “difficult” targets like protein-protein interactions (PPIs). And although there are many examples of successful MC drugs derived from natural products, there is little information about the characteristics of compounds with effective pharmacological and physicochemical properties. In this dissertation, I describe the development of design guidelines for new MC drugs based on a representative set of known inhibitor MCs and their target proteins. Analysis of both the individual MC structures and their interactions in the protein complex resulted in identification of several structural and physicochemical features likely to promote favorable binding and bioavailability. Additionally, investigation of the binding sites on the proteins suggest that MCs can bind targets conventionally considered “non-druggable,” strengthening the argument for exploring MC compounds to increase the druggable target space. Furthermore, this work includes the application of the proposed design guidelines to the development of synthetic MC libraries for a PPI target, the NEMO/IKKβ complex.