engleski

Irreversible inhibition of monoamine oxidase B enzyme. A computational insight.

Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes responsible for the regulation of amine neurotransmitter levels. This enzymes represent main pharmacological target for the treatment of depression and neurodegenerative diseases. Two isoforms of this enzyme are present in human body, MAO A and MAO B, which share about 70% of the identity in the primary sequence, but show significant differences in substrate selectivity and inhibitor specificity in particular. Focus of this work are selective irreversible inhibitors of MAO B, selegiline and rasagiline, widely used in the treatment of symptoms of Parkinson and Alzheimer disease. Both inhibitors form covalent bond with organic cofactor flavin adenine dinucleotide (FAD). In that way they prevent MAO B enzyme's further catalytic activity. Here, we used a molecular dynamics (MD) simulations, to simulate 300 ns of interaction of MAO B with both inhibitors. It is shown that Tyr398 and Tyr435 form aromatic cage responsible for interaction with aromatic part of inhibitor. Ile199 is characterized as structurally responsible for the selectivity of the inhibitor, which confirms the experimentally obtained results. Aromatic interactions between the inhibitors and the aromatic cage amino acids as well as the hydrogen bonds between the inhibitors and the flavin cofactor carbonyl oxygen O8 orient the inhibitors in a favorable position for the reaction leading to the covalent binding with the FAD inhibitor. Using MM-PBSA tools, binding free energy values were obtained. The results show that selegiline binds better than rasagiline by 1.4 kcal/mol which is consistent with experimental IC50 values. Quantum-chemical analysis within the enzyme cluster model showed that MAO inhibition proceeds through a 4-step reaction, with the first step determining the total reaction rate, in which FAD cleaves the hydride ion from the α-methylene group of the inhibitor in a complete analogy with the MAO catalytic mechanism. The resulting reaction profiles and the final structure of the inhibited enzymes are in excellent agreement with the experimental data. The obtained results are of great importance for the development of new and more effective MAO B inhibitors for clinical use.

mao b ; inhibition ; molecular dynamics ; reaction mechanism ; computational chemistry

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