engleski

Irreversible inhibition of the MAO B enzyme. A computational insight into the inactivation mechanism

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, and their metabolites from the phase one of drug metabolism. In this work we used molecular dynamics simulations to obtain insight into MAO B interactions with both inhibitors and their metabolites in the active site. It has been shown that Tyr398 and Tyr435 form an aromatic cage responsible for interactions with the aromatic part of an inhibitor. Gln206 is characterized as the active site residue most responsible for accommodating the inhibitors. The binding free energies, obtained using MM-GBSA tools, reveal that tertiary amines bind better than secondary analogues, being consistent with the experimental IC50 values. Analysis of hydrogen bonds and hydrophobic interactions in the enzyme active site shows that hydrophobic interactions are crucial for binding.Quantum-chemical analysis within 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 α-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 and psychiatric diseases.

Monoamine oxydase B ; inhibition ; MMPBSA ; DFT ; molecular dynamics

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