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Innovative Approaches to Library Design for Fragment-based Drug Discovery


Fragment-based drug discovery (FBDD) is an important technology in drug discovery that seeks to identify molecules that can inhibit targets of therapeutic relevance. Once a fragment ‘hit’ is identified, it can be elaborated into a molecule with improved inhibition and favorable pharmaceutical properties. In this thesis, several strategies to augment existing FBDD techniques are discussed. While these approaches are quite different from each other, each is rooted in fundamental inorganic chemistry and utilizes principles of coordination chemistry to address problems in FBDD. First, computational screening techniques are discussed which may help accelerate FBDD against metalloenzyme targets. This strategy aims to predict inhibitor binding to the metal-containing active site of a metalloenzyme and establish structure-activity relationships. Next, the uses of isosteres, which are molecules that seek to mimic certain molecular functionalities while modulating other properties that may be advantageous are discussed in the context of metalloenzyme FBDD. Here, a subset of carboxylic acid isosteres are evaluated for their ability to inhibit influenza endonuclease and modulate the pharmacological properties of the parent carboxylic acid-containing molecule. Next, the role of three-dimensionality in FBDD is discussed, and a library of metal complexes that is highly three-dimensional is evaluated against several protein targets. Finally, recent approaches to develop a thoroughly representative 3D library from existing compounds are discussed. Overall, this thesis aims to show how concepts in inorganic coordination chemistry can augment FBDD.

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