engleski

Computational Study of the Monoamine Oxidase B Mechanism-Based Irreversible Inhibitors

Monoamine oxidase B (MAO B) is a flavoenzyme responsible for the metabolism of endogenic and exogenic amines such as monoamine neurotransmitters whose disturbed homeostasis is implicated in the wide range of neurodegenerative pathogenesis. MAO B represents primary pharmacological target for the treatment of the Alzheimer's and Parkinson's disease. Commercial drugs, selegiline and rasagiline, are administrated with dietary restrictions and in high doses are associated with more frequent and greater intensity side effects. There is a constant market pressure for the development of new, mechanism-based MAO B inhibitors with more favourable pharmacokinetic profiles. MAO B active site is recognizable due to its "aromatic cage" that consists of three aromatic components: two tyrosines and FAD (flavine adenine dinucletiode) cofactor. Innovative approach was developed for the drug design which involves binding of the aromatic scaffolds with propagylamine core which is present in commercial drugs which target MAO enzymes. More favorable thermodynamic profiles are obtained using methods of script based molecular docking and molecular dynamics simulations. Quantum chemical cluster approach was used to acquire more optimal kinetic profiles of the inhibitory activity. Subsequent analysis indicated that new-designed molecules act in the accordance with the mechanism of the hydride abstraction mechanism, same mechanism that selegiline and rasagiline follow.

MAO B

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