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MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2019. Computational chemistry, among other things, elucidates possible drug-molecular target interactions when an algorithm is run on a molecular modelling program. Although it is just a projection of reality, it enables researchers to eliminate compounds that have no specific interaction with the chosen molecular target before expensive chemical and biological screenings are done. The combination of computational chemistry and biological chemistry redefines drug design as a more secure method of identifying target specific compounds. Novel drug design often relies on compounds isolated from natural products to produce viable leads for the treatment of various diseases and ailments. Traditional healers all over the world have used indigenous vegetation as medicine to the point that researchers have started to investigate the reported medicinal value of specific fauna or flora. Testing the major constituents of natural products may provide new drug leads and sources. Parkinson’s disease is described as a progressive neurodegenerative disease with an unknown aetiology. The depletion of the neurotransmitter, dopamine, in the striatum is responsible for the motor symptoms of Parkinson’s disease and constitutes the focus of current and novel treatment regimes. The disease onset is usually met with an occasional tremor in the hands or fingers and gradually worsens over time to complete motor dysfunctionality and mental incapacity. The unknown aetiology limits researchers to symptomatic treatments that will either mimic the effects of dopamine at dopaminergic receptors or enhance the levels of dopamine in the affected regions of the brain. One of the current treatment strategies include the use of monoamine oxidase (MAO) inhibitors. MAO is an outer-mitochondrial bound enzyme responsible for the regulation and deamination of neurotransmitters throughout the body. By inhibiting this enzyme in the central nervous system the metabolism of dopamine is reduced, and thus dopaminergic neurotransmission is enhanced. The two known isoforms of the MAO enzyme, MAO-A and MAO-B, both metabolise dopamine in the brain. The difference in substrate specificity of the two MAO isoforms provides a rationale for targeting them for different therapeutic applications. MAO-A, for example, is responsible for the degradation of serotonin, tyramine and norepinephrine. Inhibition of MAO-A is indicated for diseases such as depression and anxiety. MAO-B inhibition, on the other hand, results in a significant increase in dopamine levels in the brain, and MAO-B specific inhibitors are thus used in the treatment of Parkinson’s disease. The aim of this study was to select the major constituents or metabolites of natural products and to evaluate them as potential MAO inhibitors. The chemical structures of these compounds can then be used in future studies as possible lead compounds for the design of MAO inhibitors. The results shows that DL-kavain, from the roots of the kava plant, is a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.43 μM. DL-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 μM. Under the same experimental conditions, the known MAO inhibitor, curcumin, displays IC50 values of 5.02 μM and 2.56 μM for the inhibition of MAO-A and MAO-B, respectively. It was further established that DL-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 μM, respectively. Curcumin in turn, displays a Ki value of 3.08 μM for the inhibition of MAO-A. Other natural products that exhibited MAO inhibition were tanshinone I, myrtenol and ellagic acid. Molecular docking studies was used to investigate possible binding modes and interactions of DL-kavain and curcumin with the MAO enzymes. It may be concluded that some of the central effects (e.g. anxiolytic) of kava may be mediated by MAO inhibition. Furthermore, natural products with MAO inhibition properties may serve as leads for future studies that aims to discover high potency MAO inhibitors National Research Foundation (NRF) Masters