engleski

Computational Insight into the Catalytic Activity of Monoamine Oxidase for Targeting Neurological Diseases

Monoamine oxidase (MAO) is an FAD-dependent flavoenzyme responsible for regulating the level of biogenic amines in various parts of brain by metabolizing them to the corresponding imines. Insufficient levels of amine neurotransmitters, such as dopamine and serotonin, have been associated with the progression of many neurological diseases including Parkinson, Alzheimer and Huntington disease, and several forms of depression. That is why MAO has been a drug target for over 60 years, with the primary rationale of developing drugs to treat neuropsychiatric disorders.[1] Still, despite decades of extensive research, the precise molecular mechanisms of neither the catalytic activity nor the irreversible inhibition of MAO have yet been unambiguously determined. On the basis of quantum chemical and QM/MM calculations, we have proposed a new two-step hydride mechanism for the MAO-catalyzed oxidative deamination of amines (Scheme 1), [2] and have demonstrated that it is in agreement with all available experimental data. Calculations of the pKa values of three tyrosine residues[3, 4] revealed that MAO active site is very hydrophilic, but turns hydrophobic upon entrance of the dopamine substrate, which binds in the monocationic form. All these details should aid in designing novel MAO inhibitors as transition state analogues or in further optimization of current drugs that should both lead to more efficient antidepressants and antiparkinsonian drugs.

monoamine oxidase

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