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Abstract
Neurodegenerative diseases such as Huntington’s and Alzheimer’s diseases are incurable and are among the top ten leading causes of death globally. Though their symptoms vary, they are all multifactorial and have overlaps in their etiologies. Therefore, these diseases share common therapeutic targets. Enzymes are the key factors behind biological pathways and without their activities, a lot of metabolic reactions will not take place; therefore, they comprise a large number of pharmacological targets. My dissertation focused on enzymes on the kynurenine pathway (KP) of the tryptophan pathway (TP) that are directly involved in neurodegeneration through N-methyl-D-aspartate receptor (NMDAr) regulation and free radical generation. Kynurenine (KYN) on the KP is at the key point of the KP where it acts as a substrate of three enzymes: kynurenine aminotransferase (KAT), kynurenine monooxygenase (KMO) as well as kynureninase (KYNU). When catalyzed by KAT, KYN converts to a neuroprotective metabolite kynurenic acid (KA), when catalyzed by KNYU, KYN converts into anthranilic acid which subsequently hydroxylates into a free radical generator 3-hydroxyanthranilic acid (3-HAA), and lastly, KYNU converts to another free radical generator 3-hydroxykynurenine (3-HK) through the action of KMO which later leads to 3-HAA and a neurotoxic quinolinic acid (QA). Though KYN is a substrate for the above three enzymes, it has more affinity to KMO which makes it a great target for neurodegeneration. Inhibiting KMO has not only shown to eradicate the above neurotoxic metabolites but also shifts the KP towards neuroprotection. We have proposed several lead compounds capable of inhibiting KMO using pharmacophore modeling and structure-activity relationship. Some of these compounds not only inhibit KMO but also inhibit KYNU making them more interesting as they multitarget enzymes that are involved in the free radical generation and NMDAr agonism. In this work, we also propose a known FDA-approved NSAID agent Fenbufen to inhibit KMO in the nanomolar range, making it a viable lead compound worth drug-repurposing consideration.