engleski

Computational insight into the MAO B enzyme irreversible inhibition

Monoaminooxidases A and B (MAO A and B) are mammalian flavoenzymes responsible for regulating the levels of amine neurotransmitters. These enzymes represent the main pharmacological target in the treatment of depression and neurodegenerative diseases. Two isoforms are present in the human body, MAO A and MAO B, which share about 70% of the identical amino acids in the primary sequence but exhibit significant differences in the substrate selectivity and especially in inhibitory specificity. The focus of this work are selective irreversible MAO B inhibitors, selegiline and rasagiline, widely used in alleviating the symptoms of Parkinson's and Alzheimer's diseases. In this work we used molecular dynamics simulations (MD) to obtain insight into MAO B interactions with both inhibitors in the active site. It has been shown that Tyr398 and Tyr435 form an aromatic cage responsible for interaction with the aromatic part of the inhibitor. Ile199 is characterized as being structurally responsible for the selectivity towards inhibitors, which confirms the experimentally obtained results. The binding free energies, obtained using MM-GBSA tools, reveal that selegiline binds better than rasagiline, being consistent with the experimental IC50 values. Quantum-chemical analysis employing the enzyme cluster model suggests a completely new chemical mechanism of MAO inhibition through a 3-step reaction, whereby the first step determines the overall reaction rate in which FAD cleaves the hydride ion from the inhibitor's alpha-methylene group, being in a complete analogy with the MAO catalytic mechanism. The obtained reaction profiles and the final structure of the inhibited enzyme are consistent with the experimental data. The obtained results provide new guidelines for the development of more efficient and more effective MAO B inhibitors for clinical use in the fight against neurodegenerative diseases.

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

nije evidentirano