Prominent Neuroprotective Potential of Indole-2--methylpropargylamine: High Affinity and Irreversible Inhibition Efficiency towards Monoamine Oxidase B Revealed by Computational Scaffold Analysis.

: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. : Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. : We identified indole-2-propargylamine and indole-2--methylpropargylamine as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔ = -2.5 kcal mol) and an improved reaction exergonicity (ΔΔ = -4.3 kcal mol), together with its higher binding affinity, consistently determined by docking (ΔΔ = -0.1 kcal mol) and MM-PBSA analysis (ΔΔ = -1.5 kcal mol). : Our findings strongly advocate as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases.