Kynurenine Aminotransferases as Novel Targets in Neurodegenerative and Cognitive Disorders using Rational Drug Discovery

Abstract

This dissertation is premised on observations that kynurenine aminotransferase (KAT) isozymes play a role in neurodegenerative and cognitive disorders and has considered the probable mechanisms of action of inhibitors. This thesis used rational drug discovery in the design of novel reversible human KAT-2 inhibitors. This work is presented in publication format with six chapters. Chapter 1 includes two published papers of which the first article is about the evolution of antipsychotic drugs used in the clinic to overcome both positive and negative symptoms of schizophrenia with an emphasis on the main pharmacophore features of these drugs, and the second article is a review of KATs and their existing inhibitors. Chapter 2 presents the structural features of KAT-3 with observations on its inhibition using molecular modeling and computational studies. Chapter 3 investigates the expression, purification and crystallization of human KAT-2. Chapter 4 considers the crystal structure of human KAT-2 and properties of the active site of this enzyme, which relates to the mechanism of action of the KAT isozymes. Chapter 5 presents the design and synthesis of a novel reversible inhibitor of human KAT-2, a promising lead as assessed by an HPLC-based bioassay, as well as a study of the binding affinity by the surface plasmon resonance technique to probe further its probable mechanism of action. The final chapter, Chapter 6, summarizes the results of this research with suggestions for possible future research directions.