This project brings together a skilled team of researchers with broad expertise in computational techniques related to the brain monoaminergic systems. The goal is to provide molecular and mechanistic insights into the COVID-19 induced neurodegeneration, a disturbing medical issue currently widely discussed in the literature. The project is a collaborative effort between groups led by Dr. Robert Vianello (Croatia) and Dr. Janez Mavri (Slovenia), relying on their proven ability to work together and the quality of their past achievements. The project is centered on two critical monoamine oxidase isozymes, MAO A and MAO B, which regulate brain neurotransmitter levels and have been the central target in pharmacological interventions for neurodegeneration in the last 60 years. Our approach includes employing a range of computational methods to examine how the spike protein from different SARS-CoV-2 variants influences MAO activity, based on observations that around 36% of COVID 19 infected individuals display neurological symptoms. This involves predicting the binding affinities of spike proteins to MAOs and comparing them with those for ACE2 receptors, used by the virus to enter host cells, in order to assess the feasibility of the spike protein–MAO complex formation. The latter will be evaluated for their impact on (i) the MAO catalytic activity for neurotransmitter substrates, (ii) the potency of clinical inhibitors to inactivate MAO, (iii) the ability of L-DOPA to increase dopamine levels, and (iv) the restoration of MAO functionality by molecular oxygen, which reactivates the FAD co-factor and produces H2O2, a contributor to neurodegeneration. By comparing the results for native enzymes to those involving spike protein–MAO complexes, we hope to highlight any potential associations between brain disorders and SARS-CoV-2 infections, which, in turn, may encourage further clinical research, facilitating early diagnosis and timely therapeutic interventions.